PEDIATRICS Vol. 110 No. 6 December 2002, pp. 1193-1198
Growth and Metabolic Consequences of Bladder Augmentation in Children With Myelomeningocele and Bladder Exstrophy
Gerald C. Mingin, MD*,
,
Hiep T. Nguyen, MD*,,
Robert S. Mathias, MD,
,
John A. Shepherd, PhD*,,
David Glidden, PhD|| and
Laurence S. Baskin, MD*,
* Departments of Urology
Pediatrics
Nephrology
|| Biostatistics, University of California, San Francisco, Children’s Hospital, San Francisco, California
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ABSTRACT
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Objective. Bladder augmentation using intestinal segments is reported to cause decreased linear growth in bladder exstrophy and myelomeningocele patients. We studied changes in calcium metabolism, height, bone chemistry, and bone density in exstrophy and myelomeningocele patients after bladder augmentation.
Methods. Thirty-three patients were prospectively admitted to the Pediatric Clinical Research Center at the University of California San Francisco for 24 hours. Blood and urine were analyzed for electrolytes, and serum was obtained for markers of calcium metabolism. Dual radiograph bone densitometry of the forearm was performed. Myelomeningocele patients were compared with nonaugmented myelomeningocele patients matched by age, gender, level of defect, and ambulatory status. Exstrophy augmented patients were compared with nonaugmented exstrophy patients. The bone densities in both groups were compared with normal children. Laboratory values and percentile heights were statistically analyzed using the Student t test; bone densitometry was analyzed using the Tukey test.
Results. Twenty-two patients with myelomeningocele and 11 with bladder exstrophy were studied. Mean follow-up was 3.7 years postaugmentation (range: 1–13 years). The results indicate a significant difference in serum bicarbonate and chloride levels between myelomeningocele patients who underwent ileal augmentation and those who did not. Although this may be indicative of chronic metabolic acidosis, there was no affect on growth or bone density when compared with controls. There were no other significant differences in laboratory values, or percentile heights, nor were any differences noted in patients who underwent gastrocystoplasty. In the exstrophy group, there were no observable differences in percentile height or laboratory values between the augmented and nonaugmented group. There were no significant differences in bone density between these 2 groups when matched for age and gender. No significant difference was seen in bone density when these groups were compared with normal children.
Conclusion. Bladder augmentation is safe and does not impact negatively on the linear growth or bone densities of patients with myelomeningocele or bladder exstrophy.
Key Words: growth • bone density • bladder augmentation • myelomeningocele • exstrophy.
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INTRODUCTION
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Myelomeningocele is the most common cause of neurogenic bladder dysfunction in children. In the United States, the incidence is approximately 1 in 1000 children.1 Ninety-five percent of children with myelomeningocele have abnormal innervation of the urinary bladder.2 These children are at increased risk for renal damage because of abnormal bladder compliance, which can lead to hydronephrosis, lower urinary tract infection, and pyelonephritis. Medical treatment includes intermittent catheterization to provide adequate bladder emptying and anticholinergic medication to increase bladder compliance.3 When medical therapy fails to achieve an adequate low-pressure bladder, standard treatment has been bladder augmentation using intestinal segments (ileum, colon, and stomach).4,5 The metabolic and growth consequences of bladder augmentation have been a long-term concern, especially in children. There have been multiple reports of metabolic abnormalities as well as impaired bone growth after augmentation cystoplasty.6–12
Bladder exstrophy occurs in between 1 and 30 000 to 40 000 newborns, affecting males 3 to 4 times more often than females. This spectrum consists of classic bladder exstrophy in 
60% of patients, isolated epispadias in 30%, and cloacal exstrophy in 10%. Continence rates vary depending on the severity of the initial defect and the size of the initial bladder plate.13–15 To achieve continence, a significant number of patients require bladder augmentation, typically with an ileal intestinal segment. Intestinal augmentation in patients with bladder exstrophy has also been associated with decreased linear growth.16
Metabolic abnormalities have been reported in patients undergoing bladder augmentation. For example, the metabolic abnormalities seen in children who undergo gastrocystoplasty include hypochloremic hypokalemic metabolic alkalosis, whereas those with ileal or colonic augmentation can develop hyperchloremic hypokalemic metabolic acidosis. The later condition has been studied extensively in adults with continent cutaneous or orthotopic reservoirs6,7,17,18 and in animals with ileal and colonic augments.8,9 These studies demonstrate varying alterations in acid-base status and bone demineralization. Although most of the metabolic studies were conducted on adults, acidosis with decreased growth10–12 and decreased growth alone16 have been reported in children with neurogenic bladder and bladder exstrophy.
To assess the possible metabolic abnormalities and bone growth in our cohort of augmented children, we obtained serum and urine markers of acid-base status, calcium and bone metabolism, and dual radiograph bone densitometry measurements. Alkaline phosphatase, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D are markers of bone formation. Abnormalities associated with decreased Vitamin D include Ricketts, with loss of bone mineralization, while low levels of alkaline phosphatase are seen in renal osteodystrophy. Parathyroid hormone and osteocalcin are markers of bone reabsorption. Elevated levels are observed in osteodystrophy and osteitis fibrosa.
In children, bone mineral density is independent of age, suggesting that in growing bones an increase in bone density is caused by an increase in bone size.19 Dual radiograph bone densitometry has been shown to be a very accurate technique for measuring trabecular bone mineral content20 and is a key tool for studying bone growth soon after bladder augmentation, where changes in bone mineral content can be detected within 6 months of surgery.21
The goal of this study was to evaluate quantitatively bone growth, calcium metabolism, and height in patients with myelomeningocele and bladder exstrophy who have had bladder augmentation.
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MATERIALS AND METHODS
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This study was approved by the Committee on Human Research at the University of California, San Francisco. All patients with myelomeningocele and bladder exstrophy were asked to participate in the study by physician recruitment during routine visits to the spina bifida clinic or pediatric urology clinic at the University of California, San Francisco. Children with renal insufficiency or renal failure were excluded. Children <12 with a glomerular filtration rate below 90 mL/min/m2 and older children with glomerular filtration rate <78/81 (males and females, respectively) were excluded. Each child was admitted overnight for the study. Preoperative and postoperative heights, minimum of 3 each, were obtained from the medical chart. When information was unavailable, the child’s pediatrician was contacted.
Blood drawn for serum electrolytes, ionized calcium, alkaline phosphatase, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D, parathyroid hormone, and osteocalcin were obtained in all patients. A venous blood gas was obtained and a 24-hour urine testing was performed for creatinine clearance and urine electrolyte measurements. A plain film of the forearm to assess bone age was done to control for possible inconsistencies in bone densitometry. This was followed by dual radiograph densitometry of the forearm. Each study was performed using a QDR 4500. A dual radiograph densitometer in standard forearm scan mode using software version 910 (Hologic, Bedford, MA).
Children with myelomeningocele who were augmented with either stomach or ileum were compared with children of the same sex and age with a similar level of defect and ambulatory status. Similarly, exstrophy children who underwent bladder augmentation were compared with nonaugmented exstrophy children. The bone density measurements of augmented spina bifida and exstrophy children were also compared with children without exstrophy (Control children enrolled in a separate study at our institution with forearm bone densities measured on the Hologic QDR 4500).
Percentile heights and laboratory values were compared using the unpaired t test (P 
.05) as well as the Wilcoxon sum of ranks test. Bone densities were analyzed using the Tukey test of significance (P .05), SAS version 8.0 software (SAS, Cary, NC).
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RESULTS
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There were 13 patients in the augmented myelomeningocele group. Four boys and 3 girls with a mean age of 13 years (range: 9–25 years) underwent ileal augmentation. Two boys and 4 girls with a mean age of 13 years (range: 6–18) had gastric augments. Nine patients with myelomeningocele with a mean age of 13 years (range: 9–18) who were never augmented served as controls. The defect in all cases occurred at the lumbar-sacral level. The average time from surgery to follow-up was 3.6 years (range: 1–7).
A significant difference was seen in serum bicarbonate and chloride levels between ileal and nonaugmented myelomeningocele patients (22 mmol/L vs 27.1 mmol/L and 107.6 mmol/L vs 101.7 mmol/L, respectively). There were no other significant differences in percentile height, laboratory studies, or bone density measurements among the groups (Table 1; Fig 1). No significant difference was seen in bone mineral density between the augmented group and normal children (Fig 1, 2).
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TABLE 1. Percentile Height, Laboratory Values, and Total Bone Mineral Density of Ileal and Gastric Augmented Spina Bifida Patients Compared With Spina Bifida Control Patients
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Fig 1. Graph of average total bone mineral density among ileal and gastric augmented spina bifida patients compared with spina bifida controls and normal children.
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Fig 2. Graph of average total bone mineral density between ileal augmented bladder spina bifida patients and normal children.
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The augmented exstrophy group consisted of 7 patients. Four boys and 3 girls with an ileal patch. The mean age was 12 years (range: 6–19). There were 4 patients with exstrophy; 2 boys and 2 girls with a mean age of 8 (range: 6–13) who were not augmented and served as controls. There were no observable differences in percentile height or laboratory studies between the 2 groups (Table2). When compared with normal children there were no significant difference in mean bone density between normal controls and children augmented with ileum (Table 3 Fig 3).
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TABLE 2. Percentile Height and Laboratory Values of Ileal Augmented Bladder Exstrophy Patients Compared With Exstrophy Control Patients
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Fig 3. Graph of average total bone mineral density between ileal augmented exstrophy patients and normal children.
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Overall, there were no significant differences noted among the bone densities of the spina bifida and exstrophy groups. The mean creatine clearance in the myelomeningocele group was 120 mL/min (range: 113–148) for controls and 118 mL/min (range: 90–176) in those augmented with ileum. Exstrophy control children had a mean creatine clearance of 112 mL/min (range: 105–119), whereas those who were augmented had a mean of 97 mL/min (range: 91–104).
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DISCUSSION
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We studied the metabolic parameters of augmented spina bifida and exstrophy patients. All of the patients studied had normal serum electrolytes, with the exception of chloride, which was elevated in the ileal augmented spina bifida group. We noted a significant difference in venous pH and bicarbonate measurements between ileal augmented spina bifida patients and the controls. The bicarbonate levels were significantly lower in 6 out of 7 patients in the augmented group. This combined with a lower pH and elevated chloride is significant for metabolic acidosis. The acidosis seen in this group is subclinical, as none of the patients required alkali therapy at the time of study.
There was no evidence of deficient vitamin D stores. There were no differences observed in calcium metabolism between the groups, including the augmented group with acidosis. This is surprising, because metabolic acidosis is associated with a negative calcium balance as well as changes in phosphorus, magnesium, sodium, potassium, and chloride.6
In adults with ileal and colon conduits, serum electrolytes are normal and metabolic acidosis is mild in most cases. Vitamin D, parathyroid hormone, and plasma alkaline phosphatase are normal. However, there is disagreement, with 1 study reporting significant changes in acid base balance in the presence of both normal and abnormal electrolytes.7,17,18,22
A review of similar studies performed in animals confirms the above findings. When the bladders of both rats and dogs were either augmented or completely replaced with ileum or colon, these animals developed varying degrees of acidosis with normal serum calcium and electrolytes.8,9
Two reported studies evaluated pH and calcium metabolism in children with bladder augmentation. Wagstaff et al11 reported no difference in acid-base status or electrolytes between augmented and nonaugmented children. In the second study, all of the children were acidotic; however, serum electrolytes and 24-hour urine calcium levels were within the normal range.
Our results are in agreement with most of the mentioned studies. Although we show a metabolic acidosis in the ileal augmented spina bifida patients, serum electrolytes were normal and there is no loss of bone calcium based on 24-hour urine collection. In comparison, we do not see a hyperchloremic metabolic acidosis in exstrophy children augmented with ileum. A possible explanation for this is the small number of control patients, with larger numbers a difference might be seen. It is also possible that there is some unidentified predisposition to acidosis in the myelomeningocele population.
The second part of our study focused on measuring growth. We could find no difference in the percentile heights of those who were augmented when compared with their respective controls.
Mundy and Wagstaff et al10–12 were the first to study linear growth in children post augmentation. In the first study heights were obtained for 16 children, 6 with colocystoplasty and 10 with ileocystoplasty. Three of 6 children with a colocystoplasty showed a 20% reduction in growth. Growth charts in the 10 children with ileocystoplasty did not show any change. The authors attribute their findings to a decrease in the ability of the colon to reabsorb calcium.
Wagstaff et al11 measured heights in 60 of 183 patients. Twelve patients (20%) were reported to have delayed linear growth as defined by a change in percentile height post intestinocystoplasty.11 In a follow-up study, Wagstaff et al12 reviewed the heights of the children previously studied. Forty-five of these patients were diagnosed with exstrophy/epispadias, 9 had neuropathic bladders and the rest were miscellaneous. The mean age at the time of surgery in their study was 7.8 years. Again, they reported a 20% delay in linear growth, with a 2.5-year follow-up. However, they also reported accelerated growth in 9 (15%) of patients. The diagnosis of these patients is not reported.
Recently, Gross et al16 reviewed the preoperative and postoperative heights in their cohort of bladder exstrophy patients, status post enterocystoplasty. They report delayed growth as defined by a postoperative decrease in percentile height in 17 (83%) of patients. On average, children who underwent augmentation lost 15.6 percentile points in height. Mean follow-up was 5.7 years in the augmented patients. Mean age at surgery was 7.7 years.
Two of these studies have findings similar to our own. Mundy et al10 described no change in growth in children with ileocystoplasty, whereas only 3 children with colocystoplasty show a reduction in growth. Although the study by Wagstaff et al12 reported 12 patients with reduced growth, the study is confounded by 9 patients having an increase in linear growth. These studies also failed to identify the diagnosis of the 12 patients with decreased growth. Did these patients have bladder exstrophy or neurogenic bladder? Finally, in these 3 studies bone densitometry was not performed.
Our study may be criticized for the low percentile height of the myelomeningocele controls; however, children with spina bifida do not grow as well as normal children. Several studies have shown percentile height to be below the 10th percentile in this population. Hayes-Allen23 studied obesity among children with myelomeningocele and found that 44 of 50 children were less than the 10th percentile for height. Although their population was not subdivided according to level of the lesion, another study by Rosenblum et al24 placed their patients into groups according to the level of the lesion. They reported 50 of 99 patients to be below the third percentile in length.24 These studies are in agreement with our findings that myelomeningocele patients are at the 10th percentile for growth. In contrast, those children with bladder exstrophy with and without augmentation fall within the 75th percentile.
To obtain an objective measurement of bone mineral content, bone scans were performed. Bone densities were not significantly different among the groups. Surprisingly, augmented spina bifida patients had bone densities similar to normal children.
There is only 1 previous study evaluating bone density measurements in children after either augmentation cystoplasty or conduit surgery. Stein et al25 reported on the effects of skeletal bone density and whole body potassium up to 30 years after urinary diversion. Among these, 1 adolescent underwent ileal augmentation. The authors found no decrease in bone density. In those papers previously mentioned where adult patients underwent creation of an ileal or colon conduit, the bone densities were normal.10,17 Koch et al18 reported decreased bone densities in patients with a conduit, however there was no difference when compared with controls who were managed with intermittent catheterization.
One criticism of our findings is the rather short follow-up. It can be argued that bone demineralization may take years to develop. In the Tschopp and Koch studies,17,18 follow-up ranged from 5 to 8 years and 17 to 22 years respectively. However, changes in bone mineralization have been detected within 6 months of nonurologic surgery.21 Because all of our patients were studied >6 months post augmentation, length of follow-up is not a concern. Another criticism is our use of the forearm for bone density measurement. It has been shown that the bone mineral density of the distal radius accurately reflects systemic bone mineralization in both ambulators and nonambulators.26
Our study differs from the previous studies in an important way. Because of the small size of our study population, it is difficult to control for all variables; this is especially true regarding the exstrophy population. Despite this, our series of 22 myelomeningocele children is the largest reported comparison between sex- and age-matched patients, with a power sufficient to detect differences.
It is interesting to speculate why some investigators see a decrease in growth and others do not. One possible reason for this lies in the age at the time of surgery. The majority of our augmented spina bifida patients were older, with a mean age of 13 years old compared with a mean age of 7.7 and 7.8 for exstrophy patients in the other quoted studies. It is plausible that the older the child at the time of surgery, then the less pronounced an effect augmentation has on growth. The augmented exstrophy patients that we studied had a mean age of 8 years at the time of surgery. If the above explanation was true, we might expect to see a decrease in percentile height in these patients because they underwent augmentation at a much earlier age. However, this is not the case and may be attributable to the smaller number of exstrophy controls.
It is possible that spina bifida patients react differently from exstrophy patients postaugmentation, but it is more likely that augmentation would lead to similar changes in growth. Regardless of the impact that augmentation may have on height, there are no changes in the bone density of these children.
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CONCLUSION
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We studied 13 augmented spina bifida patients and saw a significant difference in serum bicarbonate and chloride levels in those augmented with ileum when compared with control patients. No significant difference was seen in the percentile heights or bone densities of these children. No differences were seen among those patients with a gastric augment when compared with controls. We, therefore, conclude that bladder augmentation in this population does not seem to adversely affect growth. In addition, in the augmented bladder exstrophy group no observable differences were seen in any of the parameters studied. Differences may exist that were not detected because of the small number of controls. However, no significant difference was seen in the bone density measurements of the augmented exstrophy patients when compared with normal controls. This data questions whether augmentation has a negative effect on growth in children with bladder exstrophy.
Currently, until other alternatives become available, we believe enterocystoplasty to be a safe and acceptable method for bladder augmentation in both patients with spina bifida and bladder exstrophy.
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ACKNOWLEDGMENTS
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Support for the study was through the Pediatric Clinical Research Center at the University of California, San Francisco Children’s Hospital and was sponsored by the National Institutes of Health (grant M01RR01271).
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FOOTNOTES
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Received for publication Dec 20, 2001; Accepted Jul 8, 2002.
Reprint requests to (L.S.B.) University of California, San Francisco, Children’s Hospital, 533 Parnassus Ave, U575, San Francisco, CA 94143-0738. E-mail: lbaskin{at}urol.ucsf.edu
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PEDIATRICS (ISSN 1098-4275). ©2002 by the American Academy of Pediatrics
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ABSTRACT
INTRODUCTION
