Original Paper Received: March 17, 2014 Accepted after revision: August 15, 2014 Published online: January 21, 2015
Fetal Diagn Ther DOI: 10.1159/000367805
Laser Ablation of Posterior Urethral Valves by Fetal Cystoscopy José María Martínez a Narcis Masoller a Roland Devlieger c Esther Passchyn c Olga Gómez a Joan Rodo b Jan A. Deprest c Eduard Gratacós a
a
BC Natal, Barcelona Center for Maternal-Fetal Medicine and Neonatology, Hospital Clínic and Hospital Sant Joan de Deu, IDIBAPS, University of Barcelona, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, and b Hospital Sant Joan de Déu, Barcelona, Spain; c Department of Obstetrics and Gynecology, University Hospital Gasthuisberg, Leuven, Belgium
Key Words Fetal therapy · Fetal cystoscopy · Fetoscopy · Lower urinary tract obstruction · Posterior urethral valves · Prenatal diagnosis
Abstract Objective: To report the results of fetal cystoscopic laser ablation of posterior urethral valves (PUV) in a consecutive series in two referral centers. Methods: Twenty pregnant women with a presumptive isolated PUV were treated with fetal cystoscopy under local anesthesia. Identification and fulguration of the PUV by one or several firing-contacts with diode laser were attempted. Perinatal and long-term outcomes were prospectively recorded. Results: The median gestational age at procedure was 18.1 weeks (range 15.0–25.6), and median operation time was 24 min (range 15–40). Access to the urethra was achieved in 19/20 (95%) cases, and postoperative, normalization of bladder size and amniotic fluid was observed in 16/20 (80%). Overall, there were 9 (45%) terminations of pregnancy and 11 women (55%) delivered a liveborn baby at a mean gestational age of 37.3 (29.1–40.2) weeks. No infants developed pulmonary hypoplasia and all were alive at 15–110 months. Eight (40% of all fetuses, 72.7% of newborns) had normal renal function and 3 (27.3%) had renal failure awaiting renal transplantation. Conclusion: Fetoscopic laser ablation for PUV can achieve
© 2015 S. Karger AG, Basel 1015–3837/15/0000–0000$39.50/0 E-Mail [email protected] www.karger.com/fdt
bladder decompression and amniotic fluid normalization with a single procedure in selected cases with anyhydramnios. There is still a significant risk of progression to renal failure pre or postnatally. © 2015 S. Karger AG, Basel
Introduction
Fetal lower urinary tract obstruction (LUTO) affects about 1 per 5,000 live births; about 90% of the affected infant is male [1]. The link between very enlarged fetal bladder, proximal urethral dilatation and olygoanhydramnios is highly predictive of LUTO [2, 3]. Posterior urethral valves (PUV) accounts for at least 70–80%, and the rest is due to urethral atresia or stenosis [4, 5]. However, if the diagnosis is made in the first trimester of pregnancy, the association with urethral atresia or stenosis is as high as half of the LUTO cases [1]. Prenatally diagnosed cases of PUV associated with severe oligohydramnios before the 24th week of gestation have a reported This study was supported by grants from Instituto de Salud Carlos III (ref. PI12/02230), Fondo Europeo de Desarrollo Regional de la Unión Europea ‘Una manera de hacer Europa’, and by the European Commission Seventh Framework Programme (ENDO-VV) under Grant Agreement no 251356.
Eduard Gratacós Sabino de Arana 1 ES–08028 Barcelona (Spain) E-Mail gratacos @ clinic.ub.es
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Materials and Methods This is a retrospective study including all patients with fetal diagnosis of LUTO treated by fetoscopy during a 6-year period (2007 to 2012) at the Fetal Medicine Units of Hospital Clinic, Barcelona, Spain and University Hospital Gasthuisberg, Leuven, Belgium.
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Fetal Diagn Ther DOI: 10.1159/000367805
Fig. 1. Ultrasound showing a severely distended megabladder with the ‘keyhole’ sign in a male fetus at 19 weeks’ gestation.
The presumptive diagnosis was established on the basis of a tense and hyperdistended enlarged bladder, dilation of the posterior urethra with the ‘keyhole sign’, bilateral hydronephrosis, severe olygohydramnios and male sex (fig. 1). Exclusion criteria for offering therapy were any of the following: female sex, presence of an irregular, lobulated and folded non-distended megabladder (suggestive of primary prune-belly), absence of keyhole sign, sonographic signs suggesting renal cystic dysplasia with irreversible renal failure such as hyperechogenicity and cortical cysts. The presence of other malformations or chromosomal anomalies diagnosed either before or after the intervention, or even after birth, was a criterion to exclude the case from results analysis. Serial vesicocenteses to assess the renal function were performed in some cases, but it was not considered a criterion for indication of therapy. All ultrasound examinations were performed with a Siemens Sonoline Antares (Siemens Medical Systems, Malvern, PA, USA) or a Voluson 730 Expert/E8 (GE Healthcare Technologies, Milwaukee, WI, USA) ultrasound machine with 6–2 MHz and 7–4 MHz curvedarray probes. After extensive counseling and written informed consent, procedures were approved by the local ethics committee. Fetuses were anesthetized through a single intramuscular dose of fentanyl, vecuronium and atropine, adequate to estimated fetal weight, using a 20G needle on fetal thigh. A local anesthetic was applied to the mother’s skin, subcutaneous tissue and myometrium and a cutaneous incision was performed after choosing an adequate entrance point to the uterine wall, avoiding high caliber vessels. After careful ultrasound examination of the position of the fetus and the placenta, the fetoscope was percutaneously inserted into the fetal bladder avoiding the placenta. A 2.3 × 1.2 mm sheath housing a 1.3 mm endoscope (Storz, Tuttlingen, Germany) with an operative channel, through which a 0.4 mm laser fiber was used. When required, an infusion of warmed Ringer lactate to maintain the bladder distended was used. The bladder was thoroughly examined and the diagnosis of PUV could be confirmed in every case. The fetoscope was advanced into the posterior urethra. Identification of the veru
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mortality rate of more than 90%, mainly due to pulmonary hypoplasia. Of those who survive the neonatal period, 25–30% will are likely to develop end-stage chronic renal impairment necessitating dialysis and/or transplantation [6, 7]. In the case of urethral atresia, the prognosis is even poorer, and a few survivors have been reported, all of whom required transplantation [8, 9]. Prenatal fetal bladder decompression has been proposed in selected cases of LUTO since the early 1980s, primarily to normalize amniotic fluid and prevent pulmonary hypoplasia, and secondarily to ameliorate renal parenchymal compression [10–13]. During 20 years the main treatment option was vesicoamniotic shunting, though its efficacy was never proven. Shunt has been reported to result in 40–50% survival rates, with rates of end-stage renal failure among survivors ranging 30–40%. Moreover, the rate of complications with shunting is high, gets often dislogded or obstructed, and thus requires several procedures in a high proportion of cases [14, 15]. To overcome the difficulties in assessing the actual usefulness of the procedure, a multicenter randomized trial comparing shunting with conservative management was initiated in 2006. After four years, the trial was stopped because of insufficient recruitment of cases, showing that there was a trend to a higher survival in the treated group, but with no effect in improving the chances of babies surviving with normal renal function [16]. Fetal cystoscopy and laser ablation of posterior urethral valves was proposed a decade ago as an alternative to improve the results of vesicoamniotic shunting [17– 20]. Theoretically, cystoscopic therapy addresses the mechanic problem causing the obstruction and if successful it entails a single procedure. During recent years, two series with 10 [21] and 11 [22] cases have been published. Preliminary experience results suggest that cystoscopic urethral deobstruction is feasible in a majority of cases and that it could achieve similar or slightly better results than those reported with shunt decompression [21, 22]. The aim of this study was to investigate the feasibility and safety of fetal cystoscopy, and to report a consecutive series of 20 cases of posterior urethral valves (PUV) treated prenatally by cystoscopic laser ablation in two fetal therapy units.
c d
b a b
3 Color version available online
d
Color version available online
2
Fig. 2. Endoscopic visualization of the bladder in the same case as Figure 2. Anatomical landmarks: a Verumontanum, b Plicae colliculi, c Urethral opening, d Valves. Fig. 3. Laser fulguration of the valves.
a
b
Fig. 4. Ultrasound at 4 (a) and 7 (b) days after the laser ablation, in the same case as Figure 1. There is normalization of amniotic fluid, and of the size of the bladder. The wall of the bladder is hypertrophic .
montanum was a useful landmark to identify the valves that were subsequently fired using contact laser diode energy (fig. 2 and 3). Urethral patency was examined immediately postprocedure either by catheterization or by power Doppler evaluation after instilling Ringer solution into the bladder, as has been referred [17, 20, 22]. After the operation was completed, an ultrasound follow up was performed to confirm the normalization of amniotic fluid and disappearance of the megabladder (fig. 4). Patients were usually discharged within 24–48 h after the procedure and were followed up according to standard clinical protocols. Patients delivered either in our institution or in the referring center, and hence it was possible to record the perinatal outcome in all cases. Postnatally, all neonates underwent extensive evaluation by the pediatric urologist, blood analysis of renal function and ultrasound examination. Micturition cystouretrography and postnatal cystoscopy
were performed to confirm the prenatal diagnosis of the PUV. Main outcome measures in this study were the rate of cases normalizing amniotic fluid and bladder size suggesting successful valve ablation, reappearance of olygohydramnios suggesting evolution to renal failure in utero, overall perinatal survival and longterm renal function in survivors.
Laser Ablation of Posterior Urethral Valves by Fetal Cystoscopy
Fetal Diagn Ther DOI: 10.1159/000367805
Results
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Gestational age at diagnosis ranged from 14.1 to 25.5 weeks as determined by the first trimester fetal crownrump length measurement. The median gestational age at
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Fetal Diagn Ther DOI: 10.1159/000367805
Table 1. Clinical features of PUV cases treated by cystoscopy GA at Normal Recurrence GA at Outcome cystoscopy AFI olygoA delivery/ postsurgery TOP
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
23.6 20.1 17.2 15.0 17.2 23.2 21.2 15.5 18.3 16.4 16.1 17.2 18.5 16.2 17.4 18.6 25.6 24.2 24.1 21.6
Yes Yes No No Yes Yes Yes Yes Yes Yes Yes Yes Yes No No Yes Yes Yes Yes Yes
No No – – No Yes No Yes No No No No Yes – – No No No No No
29.1 39.5 21.2 15.2 40.2 33.1 22.1 18.1 39.5 37.6 39.1 18.3 27.1 19.1 18.2 34.3 32.6 37.3 34.1 29.6
Alive and NRF Alive and NRF TOP TOP Alive and NRF Alive and CRI PROM + TOP TOP Alive and CRI Alive and NRF Alive and NRF Trisomy 21 + TOP TOP TOP TOP TOP Alive and CRI Alive and NRF Alive and NRF Alive and NRF
GA = Gestational age (in weeks); AFI = amniotic fluid index; TOP = termination of pregnancy; CRI = chronic renal insufficiency; NRF = normal renal function.
Discussion
This case series confirms that fetal cystoscopic ablation of PUV is feasible with a single procedure in a majority of cases. However, predicting postnatal renal function during intrauterine life remains a challenge. Our results are in line with the small number of studies previously reported. Quintero et al. first described cystoscopy as adjunctive diagnostic method [17, 18], and later reported a preliminary series as a therapeutic approach [19]. However, the authors combined cystoscopy with vesicoamniotic shunting in most cases, and therefore they are not comparable with the present series. Later, Welch et al. reported successful treatment in 6 of 10 fetuses with a purely cystoscopic approach with hydro-ablation or guidewire passage through the urethra [20]. More recently, Ruano et al. [22] reported 11 cases with the same approach as in this study, where results were compared with 12 cases managed expectantly. Cystoscopy showed significantly better results in terms of the survival rate (62 vs. 11%) and postnatal normal renal function (62 vs. 11%) [22]. The findings we reported are similar to those of RuMartínez/Masoller/Devlieger/Passchyn/ Gómez/Rodo/Deprest/Gratacós
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procedure was 18.1 weeks (range 15.0–25.6) and the median operative time skin to skin was 24 minutes (range 15–40). Access to the dilated posterior urethra and laser ablation was achieved in 19/20 (95%) cases. We could never confirm urethral patency immediately during the procedure neither by power Doppler evaluation nor by catheterization. After surgery, bladder spontaneous voiding and normalization of amniotic fluid were observed in 16/20 (80%) cases, whereas no improvement was observed in the remaining 4 (20%). In 3 of the 16 (18.7%) cases with apparently successful therapy, progressive anhydramnios with ultrasound suggesting renal dysplasia developed later in pregnancy. No significant intraoperative complications were detected other than urinary ascites that required intraoperative drainage in one case, and resolved spontaneously in all cases within 2–5 days. Irrespective of the normalization of the bladder dimensions, a thickened bladder wall, normally with persistently dilated ureters and pelvis persisted in most cases. There were nine (45%) terminations of pregnancy (TOP) one to four weeks after the surgery (table 1). Necropsy confirmed the diagnosis of PUV in 6/9 (66.6%) of TOP cases, including the three in which renal dysplasia was suspected because of persistent anhydramnios on postoperative follow-up. In the remaining three cases, a different condition was diagnosed: several urethral stenosis at different levels of the urethra, hypoperistalsis-microcolon-megabladder syndrome and VACTER association. The remaining eleven pregnancies delivered a liveborn baby at a mean gestational age of 37.3 (29.1–40.2) weeks. Thus, the overall survival rate was 55% (11/20). All newborns were appropriate for gestational age (range 1,310– 3,860 g). Three cases (27.3%) had to be delivered preterm due to the premature rupture of membranes (PROM). None of the newborns presented respiratory insufficiency or neonatal signs of brain damage, as assessed by both clinical examination and imaging techniques. In two cases, urethro-rectal fistula was diagnosed and repaired throughout the first year of life. Both had postnatal micturition through a permeable urethra before and after repair. At 15–110 months follow-up, all survivors were alive. Eight (40% of the initially intended to treat, 72.7% of the newborns) were doing well with normal renal function and three (27.3% of newborns) had chronic renal insufficiency and were awaiting renal transplantation. Clinical features and results of PUV cases treated by cystoscopy are shown in table 1 and in figure 5 as a flowchart.
n = 20 Fetal cystoscopy (15 + 0 to 25 + 6 week) n = 19 Successful surgery n = 16 Normal amniotic fluid n = 14 Ongoing n = 11 OK
n=1 Trisomy 21
n=3 Persistent olygoA n=1 PROM 23 weeks
n=3 OlygoA 3rd T n = 11 Liveborn
Fig. 5. Flow-chart showing the study popu-
n=1 Failed surgery
n=8 Normal renal function
n=9 TOP n=3 Renal failure
ano et al. [22]. A recent systematic review has concluded that available evidence is still small and consequently fetal cystoscopy for LUTO should still be offered as an experimental intervention. The authors suggest the need for a randomized controlled trial comparing cystoscopy with vesicoamnitoc shunting [23]. The main concern after the diagnosis of fetal LUTO is to predict the risk of chronic renal failure. Analysis of urinary metabolites to assess the fetal renal function has been widely used for the last 20 years [24]. However, a recent systematic review concluded that there is insufficient evidence to recommend such invasive analysis [25]. Before 24 weeks’ gestation and particularly in very early gestational ages, fetal urine analytes could have a low correspondence with actual fetal renal function [15, 23]. In addition, in our earlier experience urine sampling might occasionally result in complications delaying or preventing therapy, including massive ascites with bladder collapse or detachment of fetal membranes. For these reasons, we did not use routine fetal urine analyses in this series. Ultrasound parameters to predict outcome have been shown to have the highest predictive value. Particularly severe olygohydramnios [26, 27] and renal parenchyma cystic appearance and echogenicity [1, 25–27] are the features associated with better predictive accuracy. This notion has recently been confirmed in a systematic review [30]. Unfortunately, negative predictive value re-
mains low. Thus, in a proportion of cases, urethral valve obstruction is part of more complex nephrourologic disorder in which primary renal dysplasia and end-stage failure may appear in utero or later in life irrespective of bladder decompression [31, 32]. From a technical perspective, fetal cystoscopy for PUV is a very challenging procedure. It must be performed by fetal medicine specialists with advanced skills in fetal therapy and within multidisciplinary teams involving pediatric urologists. Notwithstanding this, a learning curve is unavoidable and the first procedures will always be associated with a higher number of complications. An adequate angle of entry is required to allow direct vision of the valves. This can be very difficult to achieve depending on placental and fetal position. Failure to reach the perfect angle in this study led to incidental destruction of tissue in the posterior aspect of the bladder neck and creation of a vesico-rectal fistula, albeit with no long-term consequences. Amnioinfusion may occasionally overcome fetal positioning. A distended bladder is necessary, and after a variable time, leaking to the peritoneal cavity will unavoidably start leading over time to ascites and bladder collapse. Consequently, the procedure must be quick and performed with small diameter instruments. The rate of PPROM in this and Ruano et al. series was 20 and 27.3%, respectively [21]. In spite of the small numbers, the rate compares favorably with previously report-
Laser Ablation of Posterior Urethral Valves by Fetal Cystoscopy
Fetal Diagn Ther DOI: 10.1159/000367805
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lation.
ed rates of 50% with bladder shunting, which can probably be attributed to the need of several procedures [14, 15]. Additionally, laser ablation of valves should allow a more functional bladder development and improve the incidence of voiding dysfunction seen in PUV survivors after shunting [9]. Obviously, larger clinical series would be required to confirm these hypotheses. Among the strengths of this study is that the sample size reported represents a consecutive and homogeneous series of cases. All cases had confirmed urethral valve obstruction, either postnatally or by necropsy. Among the limitations of the study, we acknowledge that this is a retrospective study with no control study group, and therefore, it might be considered difficult to conclude about the procedure. However, we believe there is enough experience with conservative management to be compared with and draw some conclusions with this new therapy. In addition, sample size was small, and this prevents meaningful comparisons for variables of clinical interest.
This initial series adds to previously reported data to suggest that successful fetoscopic laser ablation in selected cases of PUV is feasible. This surgery achieves permanent bladder deobstruction and normal amniotic fluid, in a majority of cases with a single procedure. Further experience and technological improvements might help achieving better technical results. Obviously, the rarity of PUV will render the technique here described as an exceptional procedure for most fetal therapy units, being very likely used only in the context of experienced multidisciplinary fetal surgery teams, such as in other highly uncommon fetal surgeries [33, 34]. In spite of technical success, prediction of complex forms of renal dysplasia will probably remain highly challenging, and a proportion of survivors will develop renal failure postnatally. The procedure is apparently associated with lower complication rates, and could be associated with better outcomes than bladder shunting, but larger clinical series and ideally randomized trials are required to support this contention.
References
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Fetal Diagn Ther DOI: 10.1159/000367805
9 Gonzalez R, De Filippo R, Jednak R, Spencer Barthold J: Urethral atresia: long-term outcome in 6 children who survived the neonatal period. J Urol 2001;165:2241–2244. 10 Berkowitz R, Glickmann M, Smith G, et al: Fetal urinary tract obstruction: what is the role of surgical intervention in utero? Am J Obstet Gynecol 1982;144:367–375. 11 Harrison MR, Ross NA, Noall RA: Correction of congenital hydronephrosis in utero I. The model: fetal urethral obstruction produces hydronephrosis and pulmonary hypoplasia in fetal lambs. J Pediatr Surg 1982; 17: 965–973. 12 Harrison MR, Nakayama DK, Noall RA, et al: Correction of congenital hydronephrosis in utero II: decompression reverses the effects of obstruction on the fetal lung and urinary tract. J Pediatr Surg 1983;18:247–254. 13 Golbus MS, Harrison MR, Filly RA, et al: In utero treatment of urinary tract obstruction. Am J Obstet Gynecol 1982;142:383–388. 14 Coplen DE: Prenatal intervention for hydronephrosis. J Urol 1997;157:2270–2277. 15 Clark TJ, Martin WL, Divakaran TG, et al: Prenatal bladder drainage in the management of fetal lower urinary tract obstruction: a systematic review and meta-analysis. Obstet Gynecol 2003;102:367–382. 16 Morris RK, Malin GL, Quinlan-Jones E, et al; Percutaneous vesicoamniotic shunting in Lower Urinary Tract Obstruction (PLUTO) Collaborative Group: Percutaneous vesicoamniotic shunting versus conservative management for fetal lower urinary tract obstruction
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(PLUTO): a randomised trial. Lancet 2013; 382:1496–1506. Quintero RA, Johnson MP, Romero R, et al: In-utero percutaneous cystoscopy in the management of fetal lower obstructive uropathy. Lancet 1995;346:537–540. Quintero RA, Hume R, Smith C, et al: Percutaneous fetal cystoscopy and endoscopic fulguration of posterior urethral valves. Am J Obstet Gynecol 1995;172:206–209. Quintero R, Johnson M, Muñoz H, et al: In utero endoscopic treatment of posterior urethral valves. Prenatal and Neonatal Medicine 1998;3:208–216. Welsh A, Agarwal S, Kumar S, et al: Fetal cystoscopy in the management of fetal obstructive uropathy: experience in a single European centre. Prenat Diagn 2003;23:1033–1041. Agarwal SK, Fisk NM: In utero therapy for lower urinary tract obstruction. Prenat Diagn 2001;21:970–976. Ruano R, Duarte S, Bunduki V, Giron AM, Srougi M, Zugaib M: Fetal cystoscopy for severe lower urinary tract obstruction: initial experience of a single center. Prenat Diagn 2010;30:30–39. Morris RK, Ruano R, Kilby MD: Effectiveness of fetal cystoscopy as a diagnostic and therapeutic intervention for lower urinary tract obstruction: a systematic review. Ultrasound Obstet Gynecol 2011;37:629–637. Nicolaides KH, Cheng HH, Abbas A, et al: Fetal renal defects: associated malformations and chromosomal defects. Fetal Diagn Ther 1992;7:1–11.
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1 Robyr R, Benachi A, Daikha-Dahmane F, et al: Correlation between ultrasound and anatomical findings in fetuses with lower urinary tract obstruction in the first half of pregnancy. Ultrasound Obstet Gynecol 2005;25:478– 482. 2 Kaefer M, Peters CA, Retik AB, et al: Increased renal echogenicity: a sonographic sign for differentiating between obstructive and nonobstructive etiologies of in utero bladder distension. J Urol 1997; 158: 1026– 1029. 3 McHugo J, Whittle M: Enlarged fetal bladders: aetiology, management and outcome. Prenat Diagn 2001;21:958–963. 4 Abbott JF, Levine D, Wapner R: Posterior urethral valves: inaccuracy of prenatal diagnosis. Fetal Diagn Ther 1998;13:179–183. 5 Anumba DO, Scott JE, Plant ND, et al: Diagnosis and outcome of fetal lower urinary tract obstruction in the northern region of England. Prenat Diagn 2005;25:7–13. 6 Merrill DC, Weiner CP: Urinary tract obstruction; in Fisk NM, Moise KJ Jr (eds): Fetal therapy: invasive and transplacental. Cambridge, UK, Cambridge University Press, 1997, pp 273–286. 7 Johnson MP, Freedman AL: Fetal uropathy. Curr Opin Obstet Gynecol 1999; 11: 185– 194. 8 Freedman AL, Bukowski TP, Smith CA, Evans MI, Johnson MP, Gonzalez R: Fetal therapy for obstructive uropathy: diagnosis specific outcomes. J Urol 1996;156:720–723; discussion 723–724.
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29 Crombleholme TM, Harrison MR, Golbus MS, et al: Fetal intervention in obstructive uropathy: prognostic indicators and efficacy of intervention. Am J Obstet Gynecol 1990; 162:1239–1244. 30 Morris R, Malin G, Khan K, Kilby M: Antenatal ultrasound to predict postnatal renal function in congenital lower urinary tract obstruction: systematic review of test accuracy. BJOG 2009;116:1290–1299. 31 Heikkila J, Holmberg C, Kyllonen L, Rintala R, Taskinen S: Long-term risk of end stage renal disease in patients with posterior urethral valves. J Urol 2011;186:2392–2396. 32 Sarhan O, Zaccaria I, Macher MA, et al: Longterm outcome of prenatally detected posterior urethral valves: single center study of 65 cases managed by primary valve ablation. J Urol 2008;179:307–312.
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33 Martinez JM, Castañón M, Gómez O, Prat J, Eixarch E, Bennasar M, Puerto B, Gratacós E: Evaluation of fetal vocal cords to select candidates for successful fetoscopic treatment of congenital high airway obstruction syndrome: preliminary case series. Fetal Diagn Ther 2013;34:77–84. 34 Martinez JM, Prat J, Gómez O, Crispi F, Bennasar M, Puerto B, Castañón M, Gratacós E: Decompression through tracheobronchial endoscopy of bronchial atresia presenting as massive pulmonary tumor: a new indication for fetoscopic surgery. Fetal Diagn Ther 2013; 33:69–74.
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25 Morris RK, Quinlan-Jones E, Kilby MD, Khan KS: Systematic review of accuracy of fetal urine analysis to predict poor postnatal renal function in cases of congenital urinary tract obstruction. Prenat Diagn 2007;27:900–911. 26 Mahoney BS, Callen PW, Filly RA: Fetal urethral obstruction: US evaluation. Radiology 1985;157:221–224. 27 Oliveira EA, Rabelo EA, Pereira AK, et al: Prognostic factors in prenatally-detected posterior urethral valves: a multivariate analysis. Pediatr Surg Int 2002;18:662–667. 28 Estroff JA, Mandell J, Benacerraf BR: Increased renal parenchymal echogenicity in the fetus: importance and clinical outcome. Radiology 1991;181:135–139.
Fetal Diagn Ther DOI: 10.1159/000367805
Laser Ablation of Posterior Urethral Valves by Fetal Cystoscopy José María Martínez a Narcis Masoller a Roland Devlieger c Esther Passchyn c Olga Gómez a Joan Rodo b Jan A. Deprest c Eduard Gratacós a
a
BC Natal, Barcelona Center for Maternal-Fetal Medicine and Neonatology, Hospital Clínic and Hospital Sant Joan de Deu, IDIBAPS, University of Barcelona, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, and b Hospital Sant Joan de Déu, Barcelona, Spain; c Department of Obstetrics and Gynecology, University Hospital Gasthuisberg, Leuven, Belgium
Key Words Fetal therapy · Fetal cystoscopy · Fetoscopy · Lower urinary tract obstruction · Posterior urethral valves · Prenatal diagnosis
Abstract Objective: To report the results of fetal cystoscopic laser ablation of posterior urethral valves (PUV) in a consecutive series in two referral centers. Methods: Twenty pregnant women with a presumptive isolated PUV were treated with fetal cystoscopy under local anesthesia. Identification and fulguration of the PUV by one or several firing-contacts with diode laser were attempted. Perinatal and long-term outcomes were prospectively recorded. Results: The median gestational age at procedure was 18.1 weeks (range 15.0–25.6), and median operation time was 24 min (range 15–40). Access to the urethra was achieved in 19/20 (95%) cases, and postoperative, normalization of bladder size and amniotic fluid was observed in 16/20 (80%). Overall, there were 9 (45%) terminations of pregnancy and 11 women (55%) delivered a liveborn baby at a mean gestational age of 37.3 (29.1–40.2) weeks. No infants developed pulmonary hypoplasia and all were alive at 15–110 months. Eight (40% of all fetuses, 72.7% of newborns) had normal renal function and 3 (27.3%) had renal failure awaiting renal transplantation. Conclusion: Fetoscopic laser ablation for PUV can achieve
© 2015 S. Karger AG, Basel 1015–3837/15/0000–0000$39.50/0 E-Mail [email protected] www.karger.com/fdt
bladder decompression and amniotic fluid normalization with a single procedure in selected cases with anyhydramnios. There is still a significant risk of progression to renal failure pre or postnatally. © 2015 S. Karger AG, Basel
Introduction
Fetal lower urinary tract obstruction (LUTO) affects about 1 per 5,000 live births; about 90% of the affected infant is male [1]. The link between very enlarged fetal bladder, proximal urethral dilatation and olygoanhydramnios is highly predictive of LUTO [2, 3]. Posterior urethral valves (PUV) accounts for at least 70–80%, and the rest is due to urethral atresia or stenosis [4, 5]. However, if the diagnosis is made in the first trimester of pregnancy, the association with urethral atresia or stenosis is as high as half of the LUTO cases [1]. Prenatally diagnosed cases of PUV associated with severe oligohydramnios before the 24th week of gestation have a reported This study was supported by grants from Instituto de Salud Carlos III (ref. PI12/02230), Fondo Europeo de Desarrollo Regional de la Unión Europea ‘Una manera de hacer Europa’, and by the European Commission Seventh Framework Programme (ENDO-VV) under Grant Agreement no 251356.
Eduard Gratacós Sabino de Arana 1 ES–08028 Barcelona (Spain) E-Mail gratacos @ clinic.ub.es
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Materials and Methods This is a retrospective study including all patients with fetal diagnosis of LUTO treated by fetoscopy during a 6-year period (2007 to 2012) at the Fetal Medicine Units of Hospital Clinic, Barcelona, Spain and University Hospital Gasthuisberg, Leuven, Belgium.
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Fetal Diagn Ther DOI: 10.1159/000367805
Fig. 1. Ultrasound showing a severely distended megabladder with the ‘keyhole’ sign in a male fetus at 19 weeks’ gestation.
The presumptive diagnosis was established on the basis of a tense and hyperdistended enlarged bladder, dilation of the posterior urethra with the ‘keyhole sign’, bilateral hydronephrosis, severe olygohydramnios and male sex (fig. 1). Exclusion criteria for offering therapy were any of the following: female sex, presence of an irregular, lobulated and folded non-distended megabladder (suggestive of primary prune-belly), absence of keyhole sign, sonographic signs suggesting renal cystic dysplasia with irreversible renal failure such as hyperechogenicity and cortical cysts. The presence of other malformations or chromosomal anomalies diagnosed either before or after the intervention, or even after birth, was a criterion to exclude the case from results analysis. Serial vesicocenteses to assess the renal function were performed in some cases, but it was not considered a criterion for indication of therapy. All ultrasound examinations were performed with a Siemens Sonoline Antares (Siemens Medical Systems, Malvern, PA, USA) or a Voluson 730 Expert/E8 (GE Healthcare Technologies, Milwaukee, WI, USA) ultrasound machine with 6–2 MHz and 7–4 MHz curvedarray probes. After extensive counseling and written informed consent, procedures were approved by the local ethics committee. Fetuses were anesthetized through a single intramuscular dose of fentanyl, vecuronium and atropine, adequate to estimated fetal weight, using a 20G needle on fetal thigh. A local anesthetic was applied to the mother’s skin, subcutaneous tissue and myometrium and a cutaneous incision was performed after choosing an adequate entrance point to the uterine wall, avoiding high caliber vessels. After careful ultrasound examination of the position of the fetus and the placenta, the fetoscope was percutaneously inserted into the fetal bladder avoiding the placenta. A 2.3 × 1.2 mm sheath housing a 1.3 mm endoscope (Storz, Tuttlingen, Germany) with an operative channel, through which a 0.4 mm laser fiber was used. When required, an infusion of warmed Ringer lactate to maintain the bladder distended was used. The bladder was thoroughly examined and the diagnosis of PUV could be confirmed in every case. The fetoscope was advanced into the posterior urethra. Identification of the veru
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mortality rate of more than 90%, mainly due to pulmonary hypoplasia. Of those who survive the neonatal period, 25–30% will are likely to develop end-stage chronic renal impairment necessitating dialysis and/or transplantation [6, 7]. In the case of urethral atresia, the prognosis is even poorer, and a few survivors have been reported, all of whom required transplantation [8, 9]. Prenatal fetal bladder decompression has been proposed in selected cases of LUTO since the early 1980s, primarily to normalize amniotic fluid and prevent pulmonary hypoplasia, and secondarily to ameliorate renal parenchymal compression [10–13]. During 20 years the main treatment option was vesicoamniotic shunting, though its efficacy was never proven. Shunt has been reported to result in 40–50% survival rates, with rates of end-stage renal failure among survivors ranging 30–40%. Moreover, the rate of complications with shunting is high, gets often dislogded or obstructed, and thus requires several procedures in a high proportion of cases [14, 15]. To overcome the difficulties in assessing the actual usefulness of the procedure, a multicenter randomized trial comparing shunting with conservative management was initiated in 2006. After four years, the trial was stopped because of insufficient recruitment of cases, showing that there was a trend to a higher survival in the treated group, but with no effect in improving the chances of babies surviving with normal renal function [16]. Fetal cystoscopy and laser ablation of posterior urethral valves was proposed a decade ago as an alternative to improve the results of vesicoamniotic shunting [17– 20]. Theoretically, cystoscopic therapy addresses the mechanic problem causing the obstruction and if successful it entails a single procedure. During recent years, two series with 10 [21] and 11 [22] cases have been published. Preliminary experience results suggest that cystoscopic urethral deobstruction is feasible in a majority of cases and that it could achieve similar or slightly better results than those reported with shunt decompression [21, 22]. The aim of this study was to investigate the feasibility and safety of fetal cystoscopy, and to report a consecutive series of 20 cases of posterior urethral valves (PUV) treated prenatally by cystoscopic laser ablation in two fetal therapy units.
c d
b a b
3 Color version available online
d
Color version available online
2
Fig. 2. Endoscopic visualization of the bladder in the same case as Figure 2. Anatomical landmarks: a Verumontanum, b Plicae colliculi, c Urethral opening, d Valves. Fig. 3. Laser fulguration of the valves.
a
b
Fig. 4. Ultrasound at 4 (a) and 7 (b) days after the laser ablation, in the same case as Figure 1. There is normalization of amniotic fluid, and of the size of the bladder. The wall of the bladder is hypertrophic .
montanum was a useful landmark to identify the valves that were subsequently fired using contact laser diode energy (fig. 2 and 3). Urethral patency was examined immediately postprocedure either by catheterization or by power Doppler evaluation after instilling Ringer solution into the bladder, as has been referred [17, 20, 22]. After the operation was completed, an ultrasound follow up was performed to confirm the normalization of amniotic fluid and disappearance of the megabladder (fig. 4). Patients were usually discharged within 24–48 h after the procedure and were followed up according to standard clinical protocols. Patients delivered either in our institution or in the referring center, and hence it was possible to record the perinatal outcome in all cases. Postnatally, all neonates underwent extensive evaluation by the pediatric urologist, blood analysis of renal function and ultrasound examination. Micturition cystouretrography and postnatal cystoscopy
were performed to confirm the prenatal diagnosis of the PUV. Main outcome measures in this study were the rate of cases normalizing amniotic fluid and bladder size suggesting successful valve ablation, reappearance of olygohydramnios suggesting evolution to renal failure in utero, overall perinatal survival and longterm renal function in survivors.
Laser Ablation of Posterior Urethral Valves by Fetal Cystoscopy
Fetal Diagn Ther DOI: 10.1159/000367805
Results
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Gestational age at diagnosis ranged from 14.1 to 25.5 weeks as determined by the first trimester fetal crownrump length measurement. The median gestational age at
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Fetal Diagn Ther DOI: 10.1159/000367805
Table 1. Clinical features of PUV cases treated by cystoscopy GA at Normal Recurrence GA at Outcome cystoscopy AFI olygoA delivery/ postsurgery TOP
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
23.6 20.1 17.2 15.0 17.2 23.2 21.2 15.5 18.3 16.4 16.1 17.2 18.5 16.2 17.4 18.6 25.6 24.2 24.1 21.6
Yes Yes No No Yes Yes Yes Yes Yes Yes Yes Yes Yes No No Yes Yes Yes Yes Yes
No No – – No Yes No Yes No No No No Yes – – No No No No No
29.1 39.5 21.2 15.2 40.2 33.1 22.1 18.1 39.5 37.6 39.1 18.3 27.1 19.1 18.2 34.3 32.6 37.3 34.1 29.6
Alive and NRF Alive and NRF TOP TOP Alive and NRF Alive and CRI PROM + TOP TOP Alive and CRI Alive and NRF Alive and NRF Trisomy 21 + TOP TOP TOP TOP TOP Alive and CRI Alive and NRF Alive and NRF Alive and NRF
GA = Gestational age (in weeks); AFI = amniotic fluid index; TOP = termination of pregnancy; CRI = chronic renal insufficiency; NRF = normal renal function.
Discussion
This case series confirms that fetal cystoscopic ablation of PUV is feasible with a single procedure in a majority of cases. However, predicting postnatal renal function during intrauterine life remains a challenge. Our results are in line with the small number of studies previously reported. Quintero et al. first described cystoscopy as adjunctive diagnostic method [17, 18], and later reported a preliminary series as a therapeutic approach [19]. However, the authors combined cystoscopy with vesicoamniotic shunting in most cases, and therefore they are not comparable with the present series. Later, Welch et al. reported successful treatment in 6 of 10 fetuses with a purely cystoscopic approach with hydro-ablation or guidewire passage through the urethra [20]. More recently, Ruano et al. [22] reported 11 cases with the same approach as in this study, where results were compared with 12 cases managed expectantly. Cystoscopy showed significantly better results in terms of the survival rate (62 vs. 11%) and postnatal normal renal function (62 vs. 11%) [22]. The findings we reported are similar to those of RuMartínez/Masoller/Devlieger/Passchyn/ Gómez/Rodo/Deprest/Gratacós
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procedure was 18.1 weeks (range 15.0–25.6) and the median operative time skin to skin was 24 minutes (range 15–40). Access to the dilated posterior urethra and laser ablation was achieved in 19/20 (95%) cases. We could never confirm urethral patency immediately during the procedure neither by power Doppler evaluation nor by catheterization. After surgery, bladder spontaneous voiding and normalization of amniotic fluid were observed in 16/20 (80%) cases, whereas no improvement was observed in the remaining 4 (20%). In 3 of the 16 (18.7%) cases with apparently successful therapy, progressive anhydramnios with ultrasound suggesting renal dysplasia developed later in pregnancy. No significant intraoperative complications were detected other than urinary ascites that required intraoperative drainage in one case, and resolved spontaneously in all cases within 2–5 days. Irrespective of the normalization of the bladder dimensions, a thickened bladder wall, normally with persistently dilated ureters and pelvis persisted in most cases. There were nine (45%) terminations of pregnancy (TOP) one to four weeks after the surgery (table 1). Necropsy confirmed the diagnosis of PUV in 6/9 (66.6%) of TOP cases, including the three in which renal dysplasia was suspected because of persistent anhydramnios on postoperative follow-up. In the remaining three cases, a different condition was diagnosed: several urethral stenosis at different levels of the urethra, hypoperistalsis-microcolon-megabladder syndrome and VACTER association. The remaining eleven pregnancies delivered a liveborn baby at a mean gestational age of 37.3 (29.1–40.2) weeks. Thus, the overall survival rate was 55% (11/20). All newborns were appropriate for gestational age (range 1,310– 3,860 g). Three cases (27.3%) had to be delivered preterm due to the premature rupture of membranes (PROM). None of the newborns presented respiratory insufficiency or neonatal signs of brain damage, as assessed by both clinical examination and imaging techniques. In two cases, urethro-rectal fistula was diagnosed and repaired throughout the first year of life. Both had postnatal micturition through a permeable urethra before and after repair. At 15–110 months follow-up, all survivors were alive. Eight (40% of the initially intended to treat, 72.7% of the newborns) were doing well with normal renal function and three (27.3% of newborns) had chronic renal insufficiency and were awaiting renal transplantation. Clinical features and results of PUV cases treated by cystoscopy are shown in table 1 and in figure 5 as a flowchart.
n = 20 Fetal cystoscopy (15 + 0 to 25 + 6 week) n = 19 Successful surgery n = 16 Normal amniotic fluid n = 14 Ongoing n = 11 OK
n=1 Trisomy 21
n=3 Persistent olygoA n=1 PROM 23 weeks
n=3 OlygoA 3rd T n = 11 Liveborn
Fig. 5. Flow-chart showing the study popu-
n=1 Failed surgery
n=8 Normal renal function
n=9 TOP n=3 Renal failure
ano et al. [22]. A recent systematic review has concluded that available evidence is still small and consequently fetal cystoscopy for LUTO should still be offered as an experimental intervention. The authors suggest the need for a randomized controlled trial comparing cystoscopy with vesicoamnitoc shunting [23]. The main concern after the diagnosis of fetal LUTO is to predict the risk of chronic renal failure. Analysis of urinary metabolites to assess the fetal renal function has been widely used for the last 20 years [24]. However, a recent systematic review concluded that there is insufficient evidence to recommend such invasive analysis [25]. Before 24 weeks’ gestation and particularly in very early gestational ages, fetal urine analytes could have a low correspondence with actual fetal renal function [15, 23]. In addition, in our earlier experience urine sampling might occasionally result in complications delaying or preventing therapy, including massive ascites with bladder collapse or detachment of fetal membranes. For these reasons, we did not use routine fetal urine analyses in this series. Ultrasound parameters to predict outcome have been shown to have the highest predictive value. Particularly severe olygohydramnios [26, 27] and renal parenchyma cystic appearance and echogenicity [1, 25–27] are the features associated with better predictive accuracy. This notion has recently been confirmed in a systematic review [30]. Unfortunately, negative predictive value re-
mains low. Thus, in a proportion of cases, urethral valve obstruction is part of more complex nephrourologic disorder in which primary renal dysplasia and end-stage failure may appear in utero or later in life irrespective of bladder decompression [31, 32]. From a technical perspective, fetal cystoscopy for PUV is a very challenging procedure. It must be performed by fetal medicine specialists with advanced skills in fetal therapy and within multidisciplinary teams involving pediatric urologists. Notwithstanding this, a learning curve is unavoidable and the first procedures will always be associated with a higher number of complications. An adequate angle of entry is required to allow direct vision of the valves. This can be very difficult to achieve depending on placental and fetal position. Failure to reach the perfect angle in this study led to incidental destruction of tissue in the posterior aspect of the bladder neck and creation of a vesico-rectal fistula, albeit with no long-term consequences. Amnioinfusion may occasionally overcome fetal positioning. A distended bladder is necessary, and after a variable time, leaking to the peritoneal cavity will unavoidably start leading over time to ascites and bladder collapse. Consequently, the procedure must be quick and performed with small diameter instruments. The rate of PPROM in this and Ruano et al. series was 20 and 27.3%, respectively [21]. In spite of the small numbers, the rate compares favorably with previously report-
Laser Ablation of Posterior Urethral Valves by Fetal Cystoscopy
Fetal Diagn Ther DOI: 10.1159/000367805
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lation.
ed rates of 50% with bladder shunting, which can probably be attributed to the need of several procedures [14, 15]. Additionally, laser ablation of valves should allow a more functional bladder development and improve the incidence of voiding dysfunction seen in PUV survivors after shunting [9]. Obviously, larger clinical series would be required to confirm these hypotheses. Among the strengths of this study is that the sample size reported represents a consecutive and homogeneous series of cases. All cases had confirmed urethral valve obstruction, either postnatally or by necropsy. Among the limitations of the study, we acknowledge that this is a retrospective study with no control study group, and therefore, it might be considered difficult to conclude about the procedure. However, we believe there is enough experience with conservative management to be compared with and draw some conclusions with this new therapy. In addition, sample size was small, and this prevents meaningful comparisons for variables of clinical interest.
This initial series adds to previously reported data to suggest that successful fetoscopic laser ablation in selected cases of PUV is feasible. This surgery achieves permanent bladder deobstruction and normal amniotic fluid, in a majority of cases with a single procedure. Further experience and technological improvements might help achieving better technical results. Obviously, the rarity of PUV will render the technique here described as an exceptional procedure for most fetal therapy units, being very likely used only in the context of experienced multidisciplinary fetal surgery teams, such as in other highly uncommon fetal surgeries [33, 34]. In spite of technical success, prediction of complex forms of renal dysplasia will probably remain highly challenging, and a proportion of survivors will develop renal failure postnatally. The procedure is apparently associated with lower complication rates, and could be associated with better outcomes than bladder shunting, but larger clinical series and ideally randomized trials are required to support this contention.
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Fetal Diagn Ther DOI: 10.1159/000367805
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