- Email: [email protected]
Delayed Primary Repair of Bladder Exstrophy: Ultimate Effect on Growth
Delayed Primary Repair of Bladder Exstrophy: Ultimate Effect on Growth Nima Baradaran, Raimondo M. Cervellione, Andrew A. Stec and John P. Gearhart* From the Division of Pediatric Urology, Brady Urological Institute, The Johns Hopkins Medical Institutions, Baltimore, Maryland (NB, JPG), Department of Pediatric Urology, Royal Manchester Children’s Hospital, Manchester, United Kingdom (RMC), and Department of Urology, Medical University of South Carolina, Charleston, South Carolina (AAS)
Abbreviations and Acronyms BC ⫽ bladder capacity BNR ⫽ bladder neck reconstruction Submitted for publication March 20, 2012. Study received institutional review board approval. * Correspondence: Johns Hopkins Hospital, Marburg 146, 600 N. Wolfe St., Baltimore, Maryland 21287 (telephone: 410-955-5358; FAX: 410955-0833; e-mail: [email protected]).
Purpose: Late referrals or unsuitable bladder templates often require delayed primary repair of bladder exstrophy. We investigated longitudinal bladder growth rates and eventual outcomes following this approach. Materials and Methods: After institutional review board approval, we reviewed the medical records of patients with classic bladder exstrophy who underwent neonatal or delayed (more than 30 days) primary closure at our institution between 1970 and 2006. Clinical characteristics and annual cystographic bladder capacity before the continence procedure were compared. Failed primary exstrophy repairs were excluded. Results: A total of 33 patients with available bladder capacity measurements underwent delayed exstrophy closure due to small bladder template in 18 (88% male) and late referral in 15 (80% male) at respective median ages of 305 days (range 86 to 981) and 172 days (31 to 676). They were compared to 82 patients (71% male) undergoing neonatal closure at a median of 2 days of life (range 0 to 27). Pelvic osteotomy was performed in 32 of 33 delayed closures. Longitudinal analysis of the bladder capacities demonstrated that, compared to neonatally closed cases, bladder capacities were on average 36 ml smaller in those with delayed repair due to small templates (p ⫽ 0.01) and 29 ml smaller in those with late referrals (p ⫽ 0.13). However, the rate of bladder growth did not differ significantly among the 3 groups. Conclusions: Delayed primary repair of exstrophy does not compromise the rate of bladder growth. However, children born with smaller templates will have overall smaller capacities and are less likely to undergo bladder neck reconstruction. Key Words: bladder exstrophy; growth; infant, newborn; urologic surgical procedures
2336
www.jurology.com
NEONATAL primary bladder exstrophy closure is thought to protect the bladder mucosa against environmental influences and offers the advantage of early bladder cycling leading to better bladder growth in subsequent years.1 As the prenatal diagnosis of exstrophy has improved, many newborns are being delivered at major centers where the bladder exstrophy will also
be repaired immediately after birth, which has been shown to be highly successful.2 However, prenatal diagnosis is not 100% accurate and this defect is still frequently missed. If not diagnosed prenatally, newborns need to be transferred to centers with expertise in exstrophy care and, therefore, may undergo closure in a delayed fashion. Another common reason for a de-
0022-5347/12/1886-2336/0 THE JOURNAL OF UROLOGY® © 2012 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
http://dx.doi.org/10.1016/j.juro.2012.08.037 Vol. 188, 2336-2342, December 2012 RESEARCH, INC. Printed in U.S.A.
AND
DELAYED PRIMARY REPAIR OF BLADDER EXSTROPHY
layed exstrophy closure is a bladder template that is inadequate for a safe neonatal closure.3 Postponing immediate closure in a newborn with a small and unsuitable bladder template allows the bladder to grow along with somatic growth of the child and improves the chance of a successful closure. Primary closure of a bladder with a small template increases the risk of dehiscence with known consequences concerning bladder growth and urinary continence.4 Some centers that ascribe to the complete primary repair approach to exstrophy purposely delay closure in an attempt to prevent potential vascular damage to the glans and/or corporeal bodies.5 However, the question of whether delayed primary closure inhibits bladder growth due to lack of early bladder cycling and increased environmental exposures has never been truly investigated. We examined longitudinal growth of the bladder in children who underwent delayed primary closure of bladder exstrophy due to either a small bladder template or a delayed referral, and compared bladder growth in these patients to children undergoing neonatal primary closure.
PATIENTS AND METHODS An institutional review board approved bladder exstrophy database was used to identify and retrospectively review patients born with classic bladder exstrophy between 1970 and 2006 who were treated at our institution. Patients born during this time frame were studied to allow at least 6 years of followup to assess longitudinal bladder growth. Only patients whose primary bladder closures were performed at our institution with available cystographic bladder capacity measurements between age 1 and their first continence procedure were included. A history of failed primary bladder closure was considered an exclusion criterion. Three treatment groups were identified according to the timing of bladder closure and indication for delayed closure, namely neonatal closure repaired within 30 days after birth, delayed closure repaired after 30 days due to small bladder template and delayed closure due to late referral to our institution. The decision to postpone closure was made by the primary surgeon. If, with the patient under anesthesia, the bladder was inelastic and not easily placed well into the pelvis with a single finger or was not large enough to easily accommodate the suprapubic tube and stents, the bladder template was considered unsuitable for neonatal primary closure. We retrospectively reviewed all aspects of patient care, including demographics, surgical treatment, use of osteotomy, other reconstructive operations and continence procedure, and ultimate urinary continence. Subsequent cystographic BC measurements were used to compare bladder growth trends among the 3 groups. Gravity cystogram was performed with the patient under anesthesia by instillation of contrast agent into the bladder using a 6Fr catheter at 30 cm above the symphysis while the bladder outlet was occluded by an overinflated catheter balloon to prevent leakage. The associated vesicoureteral reflux is measured
2337
and 1 cc per grade of reflux in each respective ureter is subtracted from the total BC. Statistical analysis was performed using Stata®, version 10. Descriptive statistics were compared between the 2 groups using the Mann-Whitney and chi-square tests for continuous and categorical measurements, respectively. A generalized linear regression model was used to evaluate and compare the impact of treatment group and age on BC. A p value of less than 0.05 was considered statistically significant.
RESULTS Of 740 classic bladder exstrophy cases available in the departmental database seen during the aforementioned period 18 were managed by delayed primary closure secondary to a small template, 15 were managed by delayed closure due to late referral and 82 were successfully closed neonatally. Patients whose primary closure was performed elsewhere (453), who had a history of primary closure failure (145) or who did not have repeated bladder capacity measurements available (27) were excluded. The demographic and clinical characteristics of the patient population are outlined in table 1. Children whose primary repair was electively delayed because of an unsuitable template underwent closure at an older age compared to those with delayed referral (median 10 months vs 6 months). A Cantwell-Ransley epispadias repair was performed in 23 of 28 boys (82%) at closure and pelvic osteotomy was performed in 32 of 33 patients (97%) at delayed primary repair. The only case not managed by osteotomy was closed early in the series at 31 days after birth, and had a malleable pelvis and a narrow pubic diastasis that was brought into opposition by an intrasymphyseal stitch alone. Rate of epispadias was not significantly different in children undergoing neonatal compared to delayed closure. Consecutive cystographic BC measurements with the patients under anesthesia are outlined in table 2. Median BC at each respective age is presented and compared across the 3 groups. As expected, children undergoing closure due to small bladder templates had smaller capacities compared to those undergoing neonatal closure at all yearly measurements before their continence procedure. Surprisingly, except at age 2, difference in bladder capacities between children undergoing delayed closure with normal templates and those undergoing neonatal closure did not reach a statistically significant level. The figure illustrates the predicted BC growth with age across the 3 groups. Multivariate analysis was performed to assess potential associations and confounders with the aforementioned findings. Variables included were age at closure, gender and osteotomy status, along
2338
DELAYED PRIMARY REPAIR OF BLADDER EXSTROPHY
Table 1. Demographic characteristics of patients with bladder exstrophy undergoing neonatal vs delayed primary repair Neonatal Closure Male gender: No. pts (%) p Value† Median age at closure: Days (range) p Value† Epispadias: No. pts (%) p Value† Median age at epispadias repair: Yrs (range) p Value† Pelvic osteotomy: No. pts (%) p Value† Median followup: Yrs (range) p Value†
58
(71)
2
(0–27)
42
(72)
Delayed Closure, Normal Template 12 0.7
172 (31–676) ⬍0.0001 11 0.5
1.5 (0.5–4.3)
43
(80)
(91)
1.8 (1–3.8) 0.3
(52)
14 0.013
10.7 (1.5–24)
(93)
10.8 (4.2–28) 0.6
Delayed Closure, Small Template 16 0.8
(88)
305 (86–981) ⬍0.0001 12 0.3
(75)
p Value* 0.24
0.018
0.9
1 (0.5–2.7) 0.2
0.04
18 0.001
0.26
(100)
4.2 (1.2–13.6) 0.001
0.001
* Normal compared to small template in delayed closures. † Neonatal compared to delayed closures.
with the association found between age and bladder growth/capacity. The final multivariate model yielded several results. Children undergoing delayed closure due to small template have overall 36 cc smaller bladder volumes (95% CI ⫺65 to ⫺10, p ⫽ 0.012) compared to those undergoing neonatal closure. Of the children under-
going delayed primary closure secondary to a small template the rate of annual bladder growth is not statistically significantly different between those with normal and small templates (95% CI ⫺0.02 to 0.04, p ⫽ 0.7). Children undergoing delayed closure due to late referral (normal template) have overall 29 cc smaller bladders (95% CI ⫺60 to 5, p ⫽ 0.13)
Table 2. Bladder capacity in patients with bladder exstrophy undergoing neonatal vs delayed primary repair Median Bladder Capacity by Age 1 Yr: Ml (range) p Value† No. measurements 2 Yrs: Ml (range) p Value† No. measurements 3 Yrs: Ml (range) p Value† No. measurements 4 Yrs: Ml (range) p Value† No. measurements 5 Yrs: Ml (range) p Value† No. measurements 6 Yrs: Ml (range) p Value† No. measurements
Neonatal Closure 51 (17–165) 32 110 (27–260) 43 85 (10–375) 43 92.5 (15–330) 38 100 (37–250) 39 116 (64–400) 30
* Normal compared to small template in delayed closures. † Neonatal compared to delayed closures.
Delayed Closure, Normal Template
Delayed Closure, Small Template
p Value*
44.5 (41–48) 0.46 2
33.5 (25–85) 0.30 5
0.99
50 (40–65) 0.01 9
45 (15–157) 0.02 13
0.51
62 (36–92) 0.12 10
65 (30–230) 0.18 12
0.65
65 (46–81) 0.06 8
42 (30–85) 0.05 7
0.30
104 (47–145) 0.33 9
70 (33–175) 0.04 12
0.36
88 (70–144) 0.40 5
58 (40–80) 0.03 6
0.10
DELAYED PRIMARY REPAIR OF BLADDER EXSTROPHY
2339
35 (83%) gained volitional voiding after BNR and 7 (17%) required continent diversion with bladder augmentation because of failed BNR. Nine patients (11%) were not suitable candidates for BNR, and underwent bladder augmentation and urinary diversion. Combined with BNR failures, 16 patients (19.5%) in this group needed diversion, 26 (32%) are still waiting for a continence procedure and 5 were lost to followup. In the group with normal template who underwent delayed closure 6 patients (40%) are still awaiting a continence procedure, 1 (6%) underwent a failed BNR and required diversion, and 2 (12%) underwent augmentation without BNR. Six patients in this group were lost to followup since they were international referrals and are treated locally. In the group with small template and delayed closure 1 patient (5%) was lost to followup, and 9 (50%) are still awaiting a continence procedure. Of 6 patients in this group (33%) who underwent BNR 3 experienced failure and required a diversion to achieve continence, and 3 are dry with BNR alone. Two patients (11%) were ineligible for BNR and underwent urinary diversion and bladder augmentation. Median ages of patients awaiting a continence procedure are 6.1 and 6.6 years, respectively, in the neonatal and delayed closure groups (p ⫽ 0.4).
Predicted annual bladder capacity growth in children undergoing neonatal closure (solid line) vs delayed primary closure of bladder exstrophy due to small bladder template (dotted line) or late referral (dashed line).
compared to patients undergoing neonatal closure, although the difference between the cohorts is not significant. At our institution the decision regarding age and type of continence procedure is based on patient BC, pattern of BC growth, and the motivation and desire to be dry. Additionally, a vigorous preoperative voiding training program is performed by the patient and the parents. Table 3 outlines current continence status in the patient population. Briefly in the neonatal group 42 of 82 patients (51%) underwent BNR at a median age of 5.5 years (range 3.2 to 14). Of these patients
DISCUSSION It is believed that early bladder closure leads to better bladder cycling during the newborn period and ultimately results in optimal bladder growth.6,7 This theory has been supported by desirable functional and psychological outcomes of neonatal ex-
Table 3. Continence procedure in children undergoing neonatal vs delayed primary closure of bladder exstrophy Neonatal Closure No. continence procedure (%) Successful BNR: No. (%) p Value† Yrs age at BNR: Median (range) p Value† Augmentation: No. (%) p Value† Yrs age at augmentation: Median (range) p Value† No. awaiting continence procedure (%) No. lost to followup (%)
51
(62)
35
(68.6)
Delayed Closure, Normal Template 3 0 0.016
5.46 (3.18–14)
16
8.4
(31.4)
(3.2–16)
26
(32)
5
(9)
* Normal compared to small template in delayed closures. † Neonatal compared to delayed closures. ‡ One patient had failed BNR and 2 directly underwent augmentation. § Three patients had failed BNR and 2 directly underwent augmentation.
(20) (0)
—
3 (100)‡ 0.016 6.8 (6.2–9.9) 0.6 6 (40) 6
(40)
Delayed Closure, Small Template 8 3 0.087
p Value*
(44) (37.5)
0.21
5.56 (4.8–10.3) 0.46
—
5 0.44
0.21
(27.8)§
10.8 (3.2–14.9) 0.58 9 (50) 1
(5)
0.44
2340
DELAYED PRIMARY REPAIR OF BLADDER EXSTROPHY
strophy repair.8,9 However, there are instances where neonatal closure is impossible due to unavailability of a center or surgeon familiar with exstrophy care or suboptimal newborn conditions. Previous reports from our institution have revealed that primary exstrophy repair can be successfully performed in a delayed fashion.3 However, whether this delay negatively affects bladder growth potential is unknown. According to the results of this report, children with delayed closure due to a small template have overall smaller bladders compared to their neonatally closed counterparts. When the closure delay is for reasons other than a small template, the difference in size does not reach statistical significance and decreases with age. This finding is in line with observations from other centers that routinely perform delayed closure in children with normal templates.10 Arena et al also reported no difference in bladder capacity between delayed and neonatally closed children in the first year of life.11 Another important finding is that the rate of annual bladder growth is not significantly different between the 2 delayed closure groups and the neonatally closed group. Although it is not possible to propose a causal relationship between timing of closure and ultimate bladder size, it seems that delaying closure does not impede bladder growth and the bladder reaches its maximum potential size provided that a secure closure is achieved. The observed difference in BC seems to originate from the overall smaller capacity that children with small templates are born with. In an effort to identify possible reasons for this finding our group has previously demonstrated that after adjusting for all known variables, including the time of primary closure, history of a failed primary closure is the only independent risk factor precluding the bladder from optimal growth.12 This finding is in line with current observations since delayed primary closure has been successful in all the children in this report. Additionally, while epispadias repair is known to affect bladder growth,13 there was no significant difference between epispadias rate and age at repair among the study groups. Another benefit of primary neonatal closure is minimization of environmental exposure of the bladder mucosa. Extruded bladders theoretically are at increased risk for metaplastic transformation, which is another argument in favor of primary newborn closure. However, there is no evidence in the literature that a delayed primary repair increases that risk. In fact, Cervellione et al showed that the microscopic changes in the bladder after delayed closure reverse to normal postoperatively.14 Roesch et al also observed that delayed primary closure at a median age of 8.5 weeks is not associated with de-
tectable premalignant changes or cystitis cystica and inflammation in the bladder mucosa.15 More recently, after evaluating and comparing bladder biopsies at different stages of exstrophy repair, Rubenwolf et al concluded that severe epithelial changes persist or even progress despite successful bladder closure during infancy.16 Previous data from our institution also suggest that although the cellular parameters of the bladder are correlated with functional outcome in terms of continence and ultimate growth, even in bladders with long environmental exposures due to primary closure failure no plastic changes in any of the cellular layers were observed. In addition, using electron microscopy, Mathews et al observed that the bladder at birth is relatively undifferentiated with increased collagen, decreased smooth muscle fibers and immature innervations.17 The observed higher collagen-to-smooth muscle ratio has been revealed to change after birth with somatic growth, thus improving the cellular nature of the bladder. Therefore, leaving the bladder extruded for a time does not seem to be harmful to the overall health and development of the detrusor muscle or bladder musculature, which in our view is the reason for maintained growth capacity in these bladders. The ultimate goal of exstrophy repair is to achieve urinary continence and preserve renal function. The goal of this study was to evaluate longitudinal BC. Therefore, patients who did not have annual measurements available were excluded. The number of patients who underwent a continence procedure in the delayed closure group, especially in the normal template category, was small. However, the fact that 37.5% of children in the small template group were dry with BNR alone is interesting and is the subject of further research. The pattern of successful BNR in the neonatal closure group is consistent with previous reports.18 However, the small sample size limits interpreting the findings of the delayed closure group. Inherent to most retrospective studies of rare conditions such as exstrophy, patient selection is a limitation of this series. Patients who underwent delayed primary bladder closure had smaller bladder templates than those who underwent neonatal bladder closure. Further research could verify our results in patients with exstrophy with more similar bladder templates. Also the number of BC measurements was inconsistent among the 3 patient groups, which makes direct comparison difficult. Hence, the overall difference in BC and rate of bladder growth are more reliable indicators in this study. Another limitation of this series is that there are not quantifiable measurements of detrusor contractility and compliance via urodynamic studies, so the BC measurements obtained are ideal and not true
DELAYED PRIMARY REPAIR OF BLADDER EXSTROPHY
functional capacities. The approach to measure BC in the relaxed child with gravity instillation of contrast material serves to minimize variability across measurements. While this is a limitation, it is similar to and possibly an improvement in the variability seen in capacity measurements of the awake child undergoing urodynamic study. Finally, we recognize that there is a considerable rate of loss to followup in the delayed closure group with normal templates, which poses a limitation for comparing the continence results among the 3 groups.
CONCLUSIONS Patients with small bladder templates who underwent delayed bladder closure demonstrated smaller
2341
cystographic capacities compared to those with larger bladder templates who underwent neonatal bladder closure. The timing of the closure did not modify the rate of bladder growth in this exstrophy population. The results of this study show that delayed exstrophy closure is a valid option in the bladder exstrophy armamentarium if selected by the surgeon. However, we continue to recommend neonatal closure, especially in cases diagnosed prenatally or seen early if an experienced exstrophy team exists at the referral institution. Further basic science studies are awaited to define the exact changes that occur to the bladder epithelium and musculature after birth and before definitive closure, to ensure optimal conditions for bladder growth.
REFERENCES 1. Mitchell ME: Bladder exstrophy repair: complete primary repair of exstrophy. Urology 2005; 65: 5. 2. Baird AD, Nelson CP and Gearhart JP: Modern staged repair of bladder exstrophy: a contemporary series. J Pediatr Urol 2007; 3: 311. 3. Dodson JL, Surer I, Baker LA et al: The newborn exstrophy bladder inadequate for primary closure: evaluation, management and outcome. J Urol 2001; 165: 1656. 4. Novak TE, Costello JP, Orosco R et al: Failed exstrophy closure: management and outcome. J Pediatr Urol 2009; 6: 381. 5. Cervellione RM, Husmann DA, Bivalacqua TJ et al: Penile ischemic injury in the exstrophy/ epispadias spectrum: new insights and possible mechanisms. J Pediatr Urol 2010; 6: 450. 6. Grady RW and Mitchell ME: Complete primary repair of exstrophy. J Urol 1999; 162: 1415. 7. Baker LA and Gearhart JP: The staged approach to bladder exstrophy closure and the role of osteotomies. World J Urol 1998; 16: 205. 8. Connor JP, Lattimer JK, Hensle TW et al: Primary closure of bladder exstrophy: long-term func-
tional results in 137 patients. J Pediatr Surg 1988; 23: 1102. 9. Mathews R and Gearhart JP: Modern staged reconstruction of bladder exstrophy—still the gold standard. Urology 2005; 65: 2. 10. Kiddoo DA, Carr MC, Dulczak S et al: Initial management of complex urological disorders: bladder exstrophy. Urol Clin North Am 2004; 31: 417.
14. Cervellione RM, Fishwick J, Khan T et al: Routine delayed bladder exstrophy closure. Presented at 3rd International Bladder Exstrophy Symposium, Baltimore, Maryland, October 14 –15, 2009. 15. Roesch W, Bertz S, Ebert AK et al: Mucosal changes in the exstrophic bladder: is delayed timing of reconstruction associated with premalignant changes? J Pediatr Urol, suppl, 2010; 6: S55.
11. Arena S, Fishwick J, Nappo S et al: Does delayed exstrophy repair compromise bladder growth? Presented at annual meeting of American Academy of Pediatrics, Boston, Massachusetts, October 15–18, 2011.
16. Rubenwolf P, Eder F, Ebert AK et al: Persistent histological changes in the exstrophic bladder after primary closure—a cause for concern? Presented at annual congress of European Society for Paediatric Urology, Zurich, Switzerland, May 9 –12, 2012.
12. Baradaran N, Cervellione RM, Orosco R et al: The effect of a failed initial closure on bladder growth in children with bladder exstrophy. J Urol 2011; 186: 1450.
17. Mathews R, Gosling JA and Gearhart JP: Ultrastructure of the bladder in classic exstrophy: correlation with development of continence. J Urol 2004; 172: 1446.
13. Kufner M, Gearhart JP and Mathews R: Impact of epispadias repair on bladder growth in boys with classic bladder exstrophy. J Pediatr Urol 2010; 6: 578.
18. Purves T, Novak T, King J et al: Modified Young-Dees-Leadbetter bladder neck reconstruction after exstrophy repair. J Urol 2009; 182: 1813.
EDITORIAL COMMENT In this retrospective single institution study the authors report that infants with bladder exstrophy who undergo delayed closure (because of a small bladder template or late referral) have bladder capacities during childhood that are about a third smaller than those who undergo newborn closure. However, the rate of growth following closure appears to be the same. Since formal urodynamic testing was not done, it is unclear whether these encouraging bladder capacity data also translate into
similar results in bladder compliance. The more important clinical questions that remain are whether patients with delayed closure will have similar rates of continence, successful bladder neck reconstruction and need for bladder augmentation. These data are lacking since the majority of patients in the delayed closure groups are still awaiting bladder neck reconstruction. Nevertheless, these data further support the notion that delayed closure does not have overly adverse effects on bladder function.
2342
DELAYED PRIMARY REPAIR OF BLADDER EXSTROPHY
These are timely data as many medical centers are experiencing a decreased incidence of neonatal bladder exstrophy, and the appropriateness of whether select newborns should be electively transferred to centers with more expertise in primary closure is being debated.
Earl Y. Cheng Department of Urology Lurie Children’s Hospital of Chicago Feinberg School of Medicine at Northwestern University Chicago, Illinois
REPLY BY AUTHORS In our exstrophy practice formal urodynamics are done only if the patient has a capacity appropriate for a bladder neck repair and an interest in being dry. While these data are intriguing, we still prefer to close all cases with a suitable template in the newborn period. Basic science studies by Mathews et al in a select group of patients with exstrophy demonstrate that those undergoing closure in the newborn period have better growth and ultrastruc-
tural parameters on bladder biopsy (reference 17 in article). We are currently conducting more basic science studies looking at the epithelial-detrusor interactions in bladders closed at varying times to try and sort out this interesting question posed by Cheng. Some colleagues have adopted deferring newborn closure for several months, and this approach concerns us regarding the overall effect on bladder growth and eventual function.
Abbreviations and Acronyms BC ⫽ bladder capacity BNR ⫽ bladder neck reconstruction Submitted for publication March 20, 2012. Study received institutional review board approval. * Correspondence: Johns Hopkins Hospital, Marburg 146, 600 N. Wolfe St., Baltimore, Maryland 21287 (telephone: 410-955-5358; FAX: 410955-0833; e-mail: [email protected]).
Purpose: Late referrals or unsuitable bladder templates often require delayed primary repair of bladder exstrophy. We investigated longitudinal bladder growth rates and eventual outcomes following this approach. Materials and Methods: After institutional review board approval, we reviewed the medical records of patients with classic bladder exstrophy who underwent neonatal or delayed (more than 30 days) primary closure at our institution between 1970 and 2006. Clinical characteristics and annual cystographic bladder capacity before the continence procedure were compared. Failed primary exstrophy repairs were excluded. Results: A total of 33 patients with available bladder capacity measurements underwent delayed exstrophy closure due to small bladder template in 18 (88% male) and late referral in 15 (80% male) at respective median ages of 305 days (range 86 to 981) and 172 days (31 to 676). They were compared to 82 patients (71% male) undergoing neonatal closure at a median of 2 days of life (range 0 to 27). Pelvic osteotomy was performed in 32 of 33 delayed closures. Longitudinal analysis of the bladder capacities demonstrated that, compared to neonatally closed cases, bladder capacities were on average 36 ml smaller in those with delayed repair due to small templates (p ⫽ 0.01) and 29 ml smaller in those with late referrals (p ⫽ 0.13). However, the rate of bladder growth did not differ significantly among the 3 groups. Conclusions: Delayed primary repair of exstrophy does not compromise the rate of bladder growth. However, children born with smaller templates will have overall smaller capacities and are less likely to undergo bladder neck reconstruction. Key Words: bladder exstrophy; growth; infant, newborn; urologic surgical procedures
2336
www.jurology.com
NEONATAL primary bladder exstrophy closure is thought to protect the bladder mucosa against environmental influences and offers the advantage of early bladder cycling leading to better bladder growth in subsequent years.1 As the prenatal diagnosis of exstrophy has improved, many newborns are being delivered at major centers where the bladder exstrophy will also
be repaired immediately after birth, which has been shown to be highly successful.2 However, prenatal diagnosis is not 100% accurate and this defect is still frequently missed. If not diagnosed prenatally, newborns need to be transferred to centers with expertise in exstrophy care and, therefore, may undergo closure in a delayed fashion. Another common reason for a de-
0022-5347/12/1886-2336/0 THE JOURNAL OF UROLOGY® © 2012 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
http://dx.doi.org/10.1016/j.juro.2012.08.037 Vol. 188, 2336-2342, December 2012 RESEARCH, INC. Printed in U.S.A.
AND
DELAYED PRIMARY REPAIR OF BLADDER EXSTROPHY
layed exstrophy closure is a bladder template that is inadequate for a safe neonatal closure.3 Postponing immediate closure in a newborn with a small and unsuitable bladder template allows the bladder to grow along with somatic growth of the child and improves the chance of a successful closure. Primary closure of a bladder with a small template increases the risk of dehiscence with known consequences concerning bladder growth and urinary continence.4 Some centers that ascribe to the complete primary repair approach to exstrophy purposely delay closure in an attempt to prevent potential vascular damage to the glans and/or corporeal bodies.5 However, the question of whether delayed primary closure inhibits bladder growth due to lack of early bladder cycling and increased environmental exposures has never been truly investigated. We examined longitudinal growth of the bladder in children who underwent delayed primary closure of bladder exstrophy due to either a small bladder template or a delayed referral, and compared bladder growth in these patients to children undergoing neonatal primary closure.
PATIENTS AND METHODS An institutional review board approved bladder exstrophy database was used to identify and retrospectively review patients born with classic bladder exstrophy between 1970 and 2006 who were treated at our institution. Patients born during this time frame were studied to allow at least 6 years of followup to assess longitudinal bladder growth. Only patients whose primary bladder closures were performed at our institution with available cystographic bladder capacity measurements between age 1 and their first continence procedure were included. A history of failed primary bladder closure was considered an exclusion criterion. Three treatment groups were identified according to the timing of bladder closure and indication for delayed closure, namely neonatal closure repaired within 30 days after birth, delayed closure repaired after 30 days due to small bladder template and delayed closure due to late referral to our institution. The decision to postpone closure was made by the primary surgeon. If, with the patient under anesthesia, the bladder was inelastic and not easily placed well into the pelvis with a single finger or was not large enough to easily accommodate the suprapubic tube and stents, the bladder template was considered unsuitable for neonatal primary closure. We retrospectively reviewed all aspects of patient care, including demographics, surgical treatment, use of osteotomy, other reconstructive operations and continence procedure, and ultimate urinary continence. Subsequent cystographic BC measurements were used to compare bladder growth trends among the 3 groups. Gravity cystogram was performed with the patient under anesthesia by instillation of contrast agent into the bladder using a 6Fr catheter at 30 cm above the symphysis while the bladder outlet was occluded by an overinflated catheter balloon to prevent leakage. The associated vesicoureteral reflux is measured
2337
and 1 cc per grade of reflux in each respective ureter is subtracted from the total BC. Statistical analysis was performed using Stata®, version 10. Descriptive statistics were compared between the 2 groups using the Mann-Whitney and chi-square tests for continuous and categorical measurements, respectively. A generalized linear regression model was used to evaluate and compare the impact of treatment group and age on BC. A p value of less than 0.05 was considered statistically significant.
RESULTS Of 740 classic bladder exstrophy cases available in the departmental database seen during the aforementioned period 18 were managed by delayed primary closure secondary to a small template, 15 were managed by delayed closure due to late referral and 82 were successfully closed neonatally. Patients whose primary closure was performed elsewhere (453), who had a history of primary closure failure (145) or who did not have repeated bladder capacity measurements available (27) were excluded. The demographic and clinical characteristics of the patient population are outlined in table 1. Children whose primary repair was electively delayed because of an unsuitable template underwent closure at an older age compared to those with delayed referral (median 10 months vs 6 months). A Cantwell-Ransley epispadias repair was performed in 23 of 28 boys (82%) at closure and pelvic osteotomy was performed in 32 of 33 patients (97%) at delayed primary repair. The only case not managed by osteotomy was closed early in the series at 31 days after birth, and had a malleable pelvis and a narrow pubic diastasis that was brought into opposition by an intrasymphyseal stitch alone. Rate of epispadias was not significantly different in children undergoing neonatal compared to delayed closure. Consecutive cystographic BC measurements with the patients under anesthesia are outlined in table 2. Median BC at each respective age is presented and compared across the 3 groups. As expected, children undergoing closure due to small bladder templates had smaller capacities compared to those undergoing neonatal closure at all yearly measurements before their continence procedure. Surprisingly, except at age 2, difference in bladder capacities between children undergoing delayed closure with normal templates and those undergoing neonatal closure did not reach a statistically significant level. The figure illustrates the predicted BC growth with age across the 3 groups. Multivariate analysis was performed to assess potential associations and confounders with the aforementioned findings. Variables included were age at closure, gender and osteotomy status, along
2338
DELAYED PRIMARY REPAIR OF BLADDER EXSTROPHY
Table 1. Demographic characteristics of patients with bladder exstrophy undergoing neonatal vs delayed primary repair Neonatal Closure Male gender: No. pts (%) p Value† Median age at closure: Days (range) p Value† Epispadias: No. pts (%) p Value† Median age at epispadias repair: Yrs (range) p Value† Pelvic osteotomy: No. pts (%) p Value† Median followup: Yrs (range) p Value†
58
(71)
2
(0–27)
42
(72)
Delayed Closure, Normal Template 12 0.7
172 (31–676) ⬍0.0001 11 0.5
1.5 (0.5–4.3)
43
(80)
(91)
1.8 (1–3.8) 0.3
(52)
14 0.013
10.7 (1.5–24)
(93)
10.8 (4.2–28) 0.6
Delayed Closure, Small Template 16 0.8
(88)
305 (86–981) ⬍0.0001 12 0.3
(75)
p Value* 0.24
0.018
0.9
1 (0.5–2.7) 0.2
0.04
18 0.001
0.26
(100)
4.2 (1.2–13.6) 0.001
0.001
* Normal compared to small template in delayed closures. † Neonatal compared to delayed closures.
with the association found between age and bladder growth/capacity. The final multivariate model yielded several results. Children undergoing delayed closure due to small template have overall 36 cc smaller bladder volumes (95% CI ⫺65 to ⫺10, p ⫽ 0.012) compared to those undergoing neonatal closure. Of the children under-
going delayed primary closure secondary to a small template the rate of annual bladder growth is not statistically significantly different between those with normal and small templates (95% CI ⫺0.02 to 0.04, p ⫽ 0.7). Children undergoing delayed closure due to late referral (normal template) have overall 29 cc smaller bladders (95% CI ⫺60 to 5, p ⫽ 0.13)
Table 2. Bladder capacity in patients with bladder exstrophy undergoing neonatal vs delayed primary repair Median Bladder Capacity by Age 1 Yr: Ml (range) p Value† No. measurements 2 Yrs: Ml (range) p Value† No. measurements 3 Yrs: Ml (range) p Value† No. measurements 4 Yrs: Ml (range) p Value† No. measurements 5 Yrs: Ml (range) p Value† No. measurements 6 Yrs: Ml (range) p Value† No. measurements
Neonatal Closure 51 (17–165) 32 110 (27–260) 43 85 (10–375) 43 92.5 (15–330) 38 100 (37–250) 39 116 (64–400) 30
* Normal compared to small template in delayed closures. † Neonatal compared to delayed closures.
Delayed Closure, Normal Template
Delayed Closure, Small Template
p Value*
44.5 (41–48) 0.46 2
33.5 (25–85) 0.30 5
0.99
50 (40–65) 0.01 9
45 (15–157) 0.02 13
0.51
62 (36–92) 0.12 10
65 (30–230) 0.18 12
0.65
65 (46–81) 0.06 8
42 (30–85) 0.05 7
0.30
104 (47–145) 0.33 9
70 (33–175) 0.04 12
0.36
88 (70–144) 0.40 5
58 (40–80) 0.03 6
0.10
DELAYED PRIMARY REPAIR OF BLADDER EXSTROPHY
2339
35 (83%) gained volitional voiding after BNR and 7 (17%) required continent diversion with bladder augmentation because of failed BNR. Nine patients (11%) were not suitable candidates for BNR, and underwent bladder augmentation and urinary diversion. Combined with BNR failures, 16 patients (19.5%) in this group needed diversion, 26 (32%) are still waiting for a continence procedure and 5 were lost to followup. In the group with normal template who underwent delayed closure 6 patients (40%) are still awaiting a continence procedure, 1 (6%) underwent a failed BNR and required diversion, and 2 (12%) underwent augmentation without BNR. Six patients in this group were lost to followup since they were international referrals and are treated locally. In the group with small template and delayed closure 1 patient (5%) was lost to followup, and 9 (50%) are still awaiting a continence procedure. Of 6 patients in this group (33%) who underwent BNR 3 experienced failure and required a diversion to achieve continence, and 3 are dry with BNR alone. Two patients (11%) were ineligible for BNR and underwent urinary diversion and bladder augmentation. Median ages of patients awaiting a continence procedure are 6.1 and 6.6 years, respectively, in the neonatal and delayed closure groups (p ⫽ 0.4).
Predicted annual bladder capacity growth in children undergoing neonatal closure (solid line) vs delayed primary closure of bladder exstrophy due to small bladder template (dotted line) or late referral (dashed line).
compared to patients undergoing neonatal closure, although the difference between the cohorts is not significant. At our institution the decision regarding age and type of continence procedure is based on patient BC, pattern of BC growth, and the motivation and desire to be dry. Additionally, a vigorous preoperative voiding training program is performed by the patient and the parents. Table 3 outlines current continence status in the patient population. Briefly in the neonatal group 42 of 82 patients (51%) underwent BNR at a median age of 5.5 years (range 3.2 to 14). Of these patients
DISCUSSION It is believed that early bladder closure leads to better bladder cycling during the newborn period and ultimately results in optimal bladder growth.6,7 This theory has been supported by desirable functional and psychological outcomes of neonatal ex-
Table 3. Continence procedure in children undergoing neonatal vs delayed primary closure of bladder exstrophy Neonatal Closure No. continence procedure (%) Successful BNR: No. (%) p Value† Yrs age at BNR: Median (range) p Value† Augmentation: No. (%) p Value† Yrs age at augmentation: Median (range) p Value† No. awaiting continence procedure (%) No. lost to followup (%)
51
(62)
35
(68.6)
Delayed Closure, Normal Template 3 0 0.016
5.46 (3.18–14)
16
8.4
(31.4)
(3.2–16)
26
(32)
5
(9)
* Normal compared to small template in delayed closures. † Neonatal compared to delayed closures. ‡ One patient had failed BNR and 2 directly underwent augmentation. § Three patients had failed BNR and 2 directly underwent augmentation.
(20) (0)
—
3 (100)‡ 0.016 6.8 (6.2–9.9) 0.6 6 (40) 6
(40)
Delayed Closure, Small Template 8 3 0.087
p Value*
(44) (37.5)
0.21
5.56 (4.8–10.3) 0.46
—
5 0.44
0.21
(27.8)§
10.8 (3.2–14.9) 0.58 9 (50) 1
(5)
0.44
2340
DELAYED PRIMARY REPAIR OF BLADDER EXSTROPHY
strophy repair.8,9 However, there are instances where neonatal closure is impossible due to unavailability of a center or surgeon familiar with exstrophy care or suboptimal newborn conditions. Previous reports from our institution have revealed that primary exstrophy repair can be successfully performed in a delayed fashion.3 However, whether this delay negatively affects bladder growth potential is unknown. According to the results of this report, children with delayed closure due to a small template have overall smaller bladders compared to their neonatally closed counterparts. When the closure delay is for reasons other than a small template, the difference in size does not reach statistical significance and decreases with age. This finding is in line with observations from other centers that routinely perform delayed closure in children with normal templates.10 Arena et al also reported no difference in bladder capacity between delayed and neonatally closed children in the first year of life.11 Another important finding is that the rate of annual bladder growth is not significantly different between the 2 delayed closure groups and the neonatally closed group. Although it is not possible to propose a causal relationship between timing of closure and ultimate bladder size, it seems that delaying closure does not impede bladder growth and the bladder reaches its maximum potential size provided that a secure closure is achieved. The observed difference in BC seems to originate from the overall smaller capacity that children with small templates are born with. In an effort to identify possible reasons for this finding our group has previously demonstrated that after adjusting for all known variables, including the time of primary closure, history of a failed primary closure is the only independent risk factor precluding the bladder from optimal growth.12 This finding is in line with current observations since delayed primary closure has been successful in all the children in this report. Additionally, while epispadias repair is known to affect bladder growth,13 there was no significant difference between epispadias rate and age at repair among the study groups. Another benefit of primary neonatal closure is minimization of environmental exposure of the bladder mucosa. Extruded bladders theoretically are at increased risk for metaplastic transformation, which is another argument in favor of primary newborn closure. However, there is no evidence in the literature that a delayed primary repair increases that risk. In fact, Cervellione et al showed that the microscopic changes in the bladder after delayed closure reverse to normal postoperatively.14 Roesch et al also observed that delayed primary closure at a median age of 8.5 weeks is not associated with de-
tectable premalignant changes or cystitis cystica and inflammation in the bladder mucosa.15 More recently, after evaluating and comparing bladder biopsies at different stages of exstrophy repair, Rubenwolf et al concluded that severe epithelial changes persist or even progress despite successful bladder closure during infancy.16 Previous data from our institution also suggest that although the cellular parameters of the bladder are correlated with functional outcome in terms of continence and ultimate growth, even in bladders with long environmental exposures due to primary closure failure no plastic changes in any of the cellular layers were observed. In addition, using electron microscopy, Mathews et al observed that the bladder at birth is relatively undifferentiated with increased collagen, decreased smooth muscle fibers and immature innervations.17 The observed higher collagen-to-smooth muscle ratio has been revealed to change after birth with somatic growth, thus improving the cellular nature of the bladder. Therefore, leaving the bladder extruded for a time does not seem to be harmful to the overall health and development of the detrusor muscle or bladder musculature, which in our view is the reason for maintained growth capacity in these bladders. The ultimate goal of exstrophy repair is to achieve urinary continence and preserve renal function. The goal of this study was to evaluate longitudinal BC. Therefore, patients who did not have annual measurements available were excluded. The number of patients who underwent a continence procedure in the delayed closure group, especially in the normal template category, was small. However, the fact that 37.5% of children in the small template group were dry with BNR alone is interesting and is the subject of further research. The pattern of successful BNR in the neonatal closure group is consistent with previous reports.18 However, the small sample size limits interpreting the findings of the delayed closure group. Inherent to most retrospective studies of rare conditions such as exstrophy, patient selection is a limitation of this series. Patients who underwent delayed primary bladder closure had smaller bladder templates than those who underwent neonatal bladder closure. Further research could verify our results in patients with exstrophy with more similar bladder templates. Also the number of BC measurements was inconsistent among the 3 patient groups, which makes direct comparison difficult. Hence, the overall difference in BC and rate of bladder growth are more reliable indicators in this study. Another limitation of this series is that there are not quantifiable measurements of detrusor contractility and compliance via urodynamic studies, so the BC measurements obtained are ideal and not true
DELAYED PRIMARY REPAIR OF BLADDER EXSTROPHY
functional capacities. The approach to measure BC in the relaxed child with gravity instillation of contrast material serves to minimize variability across measurements. While this is a limitation, it is similar to and possibly an improvement in the variability seen in capacity measurements of the awake child undergoing urodynamic study. Finally, we recognize that there is a considerable rate of loss to followup in the delayed closure group with normal templates, which poses a limitation for comparing the continence results among the 3 groups.
CONCLUSIONS Patients with small bladder templates who underwent delayed bladder closure demonstrated smaller
2341
cystographic capacities compared to those with larger bladder templates who underwent neonatal bladder closure. The timing of the closure did not modify the rate of bladder growth in this exstrophy population. The results of this study show that delayed exstrophy closure is a valid option in the bladder exstrophy armamentarium if selected by the surgeon. However, we continue to recommend neonatal closure, especially in cases diagnosed prenatally or seen early if an experienced exstrophy team exists at the referral institution. Further basic science studies are awaited to define the exact changes that occur to the bladder epithelium and musculature after birth and before definitive closure, to ensure optimal conditions for bladder growth.
REFERENCES 1. Mitchell ME: Bladder exstrophy repair: complete primary repair of exstrophy. Urology 2005; 65: 5. 2. Baird AD, Nelson CP and Gearhart JP: Modern staged repair of bladder exstrophy: a contemporary series. J Pediatr Urol 2007; 3: 311. 3. Dodson JL, Surer I, Baker LA et al: The newborn exstrophy bladder inadequate for primary closure: evaluation, management and outcome. J Urol 2001; 165: 1656. 4. Novak TE, Costello JP, Orosco R et al: Failed exstrophy closure: management and outcome. J Pediatr Urol 2009; 6: 381. 5. Cervellione RM, Husmann DA, Bivalacqua TJ et al: Penile ischemic injury in the exstrophy/ epispadias spectrum: new insights and possible mechanisms. J Pediatr Urol 2010; 6: 450. 6. Grady RW and Mitchell ME: Complete primary repair of exstrophy. J Urol 1999; 162: 1415. 7. Baker LA and Gearhart JP: The staged approach to bladder exstrophy closure and the role of osteotomies. World J Urol 1998; 16: 205. 8. Connor JP, Lattimer JK, Hensle TW et al: Primary closure of bladder exstrophy: long-term func-
tional results in 137 patients. J Pediatr Surg 1988; 23: 1102. 9. Mathews R and Gearhart JP: Modern staged reconstruction of bladder exstrophy—still the gold standard. Urology 2005; 65: 2. 10. Kiddoo DA, Carr MC, Dulczak S et al: Initial management of complex urological disorders: bladder exstrophy. Urol Clin North Am 2004; 31: 417.
14. Cervellione RM, Fishwick J, Khan T et al: Routine delayed bladder exstrophy closure. Presented at 3rd International Bladder Exstrophy Symposium, Baltimore, Maryland, October 14 –15, 2009. 15. Roesch W, Bertz S, Ebert AK et al: Mucosal changes in the exstrophic bladder: is delayed timing of reconstruction associated with premalignant changes? J Pediatr Urol, suppl, 2010; 6: S55.
11. Arena S, Fishwick J, Nappo S et al: Does delayed exstrophy repair compromise bladder growth? Presented at annual meeting of American Academy of Pediatrics, Boston, Massachusetts, October 15–18, 2011.
16. Rubenwolf P, Eder F, Ebert AK et al: Persistent histological changes in the exstrophic bladder after primary closure—a cause for concern? Presented at annual congress of European Society for Paediatric Urology, Zurich, Switzerland, May 9 –12, 2012.
12. Baradaran N, Cervellione RM, Orosco R et al: The effect of a failed initial closure on bladder growth in children with bladder exstrophy. J Urol 2011; 186: 1450.
17. Mathews R, Gosling JA and Gearhart JP: Ultrastructure of the bladder in classic exstrophy: correlation with development of continence. J Urol 2004; 172: 1446.
13. Kufner M, Gearhart JP and Mathews R: Impact of epispadias repair on bladder growth in boys with classic bladder exstrophy. J Pediatr Urol 2010; 6: 578.
18. Purves T, Novak T, King J et al: Modified Young-Dees-Leadbetter bladder neck reconstruction after exstrophy repair. J Urol 2009; 182: 1813.
EDITORIAL COMMENT In this retrospective single institution study the authors report that infants with bladder exstrophy who undergo delayed closure (because of a small bladder template or late referral) have bladder capacities during childhood that are about a third smaller than those who undergo newborn closure. However, the rate of growth following closure appears to be the same. Since formal urodynamic testing was not done, it is unclear whether these encouraging bladder capacity data also translate into
similar results in bladder compliance. The more important clinical questions that remain are whether patients with delayed closure will have similar rates of continence, successful bladder neck reconstruction and need for bladder augmentation. These data are lacking since the majority of patients in the delayed closure groups are still awaiting bladder neck reconstruction. Nevertheless, these data further support the notion that delayed closure does not have overly adverse effects on bladder function.
2342
DELAYED PRIMARY REPAIR OF BLADDER EXSTROPHY
These are timely data as many medical centers are experiencing a decreased incidence of neonatal bladder exstrophy, and the appropriateness of whether select newborns should be electively transferred to centers with more expertise in primary closure is being debated.
Earl Y. Cheng Department of Urology Lurie Children’s Hospital of Chicago Feinberg School of Medicine at Northwestern University Chicago, Illinois
REPLY BY AUTHORS In our exstrophy practice formal urodynamics are done only if the patient has a capacity appropriate for a bladder neck repair and an interest in being dry. While these data are intriguing, we still prefer to close all cases with a suitable template in the newborn period. Basic science studies by Mathews et al in a select group of patients with exstrophy demonstrate that those undergoing closure in the newborn period have better growth and ultrastruc-
tural parameters on bladder biopsy (reference 17 in article). We are currently conducting more basic science studies looking at the epithelial-detrusor interactions in bladders closed at varying times to try and sort out this interesting question posed by Cheng. Some colleagues have adopted deferring newborn closure for several months, and this approach concerns us regarding the overall effect on bladder growth and eventual function.