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CONTEMPORARY EPIDEMIOLOGY OF BLADDER EXSTROPHY IN THE UNITED STATES
0022-5347/05/1735-1728/0 THE JOURNAL OF UROLOGY® Copyright © 2005 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 173, 1728 –1731, May 2005 Printed in U.S.A.
DOI: 10.1097/01.ju.0000154821.21521.9b
CONTEMPORARY EPIDEMIOLOGY OF BLADDER EXSTROPHY IN THE UNITED STATES CALEB P. NELSON, RODNEY L. DUNN
AND
JOHN T. WEI*
From the Department of Urology, University of Michigan, Ann Arbor, Michigan, and Brady Urological Institute (CPN), Johns Hopkins Hospital, Baltimore, Maryland
ABSTRACT
Purpose: Although bladder exstrophy is much discussed in the urology literature, there are few population based epidemiological data available for this rare condition. The purpose of this study was to use a large nationwide database to collect contemporary data on the incidence and demographics of bladder exstrophy. Materials and Methods: The Healthcare Cost and Utilization Project Nationwide Inpatient Sample is a 20% sample of nonfederal United States hospitals containing data on 5 million to 7 million inpatient stays per year. The sample was limited to newborns, and International Classification of Disease-9 codes were used to identify cases of bladder exstrophy. We then determined nationally weighted incidence through time, and performed multivariate analyses to identify factors associated with exstrophy. Results: We identified 205 patients with exstrophy among 9,452,110 newborns. The overall weighted incidence of exstrophy was 2.15 per 100,000 live births. The male-to-female ratio was almost even (OR 0.989, 95% CI 0.88 to 1.12). White infants were significantly more likely to present with exstrophy than nonwhites (incidence 2.63 vs 1.54 per 100,000, p ⬍0.0001). Exstrophy incidence also varied by geographic region, socioeconomic status (SES) and insurance status. On multivariate analysis the racial variation in exstrophy incidence persisted even after adjustment for geographic region, SES and insurance status. Conditions such as spina bifida, cleft palate, preterm birth and gastrointestinal anomalies were more common in newborns with exstrophy. Conclusions: Bladder exstrophy is rare, occurs in equal numbers of live male and female newborns, and is associated with certain co-morbid conditions. Incidence appears to be stable through time. Nonwhite race, uninsured status, high or low SES and Western geographic region are associated with lower exstrophy incidence. KEY WORDS: bladder exstrophy, epidemiology, demography
Bladder exstrophy remains one of the most challenging conditions managed by pediatric urologists. Although rare, this disorder imposes significant physical, functional, social, sexual and psychological burdens on patients and families. For the health care system the multiple, lengthy and complex operative procedures that patients with exstrophy undergo consume resources disproportionate to the small number of affected individuals. From a reconstructive perspective exstrophy poses unique challenges in the quest to achieve anatomically, functionally and cosmetically satisfactory results. Successive generations of surgeons have taken up the challenge of exstrophy and made great strides in the quest for successful outcomes, yet we remain far from a cure for this condition. One difficulty in the study of rare conditions such as bladder exstrophy is that individual institutions rarely see adequate numbers of patients to draw useful evidence based conclusions. The literature is replete with surgical case series but these are biased by selection and often span decades in time. True population based epidemiological data regarding bladder exstrophy tend to be old1 or regional in scope.2 Hence, contemporary national data are unavailable and little is known regarding demographic characteristics of the affected population. The purpose of this study was to use a nationally repre-
sentative database of inpatient hospitalizations to determine the incidence of and identify demographic factors associated with bladder exstrophy. Secondarily we sought to quantify the frequency of concomitant conditions in newborns with bladder exstrophy. MATERIALS AND METHODS
Nationwide Inpatient Sample (NIS). The NIS is part of the Healthcare Cost and Utilization Project and is the largest all payer inpatient care database that is publicly available in the United States. Each year the NIS provides information on approximately 5 million to 7 million inpatient stays from about 1,000 hospitals, and is designed to approximate a 20% sample of United States nonfederal community hospitals, including specialty hospitals, public hospitals and academic medical centers. Excluded are short-term rehabilitation and long-term, psychiatric and chemical dependency treatment facilities. The data on individual patients include age, diagnosis, procedures and disposition, as well as hospitalization data such as admission type, timing, payer and charges, and information about each hospital that participated in the NIS. Datasets for 1988 through 2000 were merged to create a single dataset containing information on all hospital admissions for this period. Univariate and multivariate analyses were then performed to examine national trends in bladder exstrophy. Epidemiological data analysis. To determine incidence rates of bladder exstrophy, it was necessary to identify new-
Submitted for publication October 25, 2004. * Financial interest and/or other relationship with Sanofi, Laserscope, Calypso and Boehringer Ingelheim. 1728
1729
CONTEMPORARY EPIDEMIOLOGY OF BLADDER EXSTROPHY IN UNITED STATES TABLE 1. Relative weighted incidence of comorbid conditions among newborns with and without exstrophy Weighted Incidence/100 Liveborn Pts With Exstrophy
Comorbid Condition
Weighted Incidence/100 Liveborn Pts Without Exstrophy
OR (95% CI)
Lower gastrointestinal anomalies* 19.3 0.13 188.6 (162–219) Preterm birth† 17.5 6.7 3.0 (2.5–3.5) Orthopedic anomalies‡ 13.2 1.2 13.1 (11.0–15.6) Spina bifida§ 6.8 0.03 224.3 (177–284) Vascular anomalies㛳 4.6 1.1 4.4 (3.3–5.8) Cardiac amomalies¶ 3.4 0.8 4.5 (3.2–6.3) Chromosomal anomalies** 1.1 0.15 7.7 (4.3–13.6) Cleft lip and/or palate†† 1.1 0.13 8.0 (4.4–14.3) * ICD-9 code 751.xx (congenital anomalies of small bowel, eg Meckel’s diverticulum, large bowel, eg Hirschsprung disease, rectum or anus, eg stenosis or imperforate anus). † ICD-9 code 765.0x (extreme immaturity), 765.1x (other preterm newborns), 765.21 to 765.28 (birth before 37 weeks of gestation). ‡ ICD-9 code 754.xx (congenital anomalies of skull, spine, hip, long bones, feet), 755.xx (polydactyly, syndactyly, reduction deformities of limbs). § ICD-9 code 741.xx. 㛳 ICD-9 code 747.xx (eg patent ductus arteriosus, coarctation of aorta). ¶ ICD-9 code 745.xx (eg transposition, tetralogy of Fallot, ventriculoseptal defect), 746.xx (eg cardiac valve anomalies, hypoplastic left heart). ** ICD-9 code 758.xx. †† ICD-9 code 749.xx.
borns. Because the NIS is a database of inpatient discharges, and because patients with bladder exstrophy are transferred between hospitals during the early days of life at a much higher rate than newborns without major congenital anomalies, it is possible that individual patients could appear multiple times in the database, artificially inflating the calculated incidence of exstrophy. To eliminate this concern as much as possible, we used a multistep extraction procedure designed to limit the working dataset to initial newborn hospitalizations. We initially extracted all hospital discharges in which the International Classification of Disease (ICD)-9 diagnosis code V3x.0 (live births in hospital, with or without 1 or more siblings) or V3x.1 (live births before hospitalization, with or without 1 or more siblings) was recorded in 1 of the 15 diagnosis slots. The “before admission” codes (V3x.1x) were included to capture any patients born outside the hospital (eg at home) and then admitted shortly thereafter. Since a small fraction (0.2%) of the patients meeting these criteria were transferred from other health care facilities, we further limited the dataset to those whose “admission source” (variable “asource” in the NIS) was not listed as either “transfer from another acute-care hospital” or “transfer from another
health-care facility.” Finally, we limited these data to patients younger than 2 days at the time of hospitalization. We then identified those patients within this dataset as having bladder exstrophy, based on the presence of ICD-9 code “753.5” in any of the 15 diagnosis slots. (Since there is no discrete ICD-9 code for cloacal exstrophy, it is possible that patients with that diagnosis are included in the sample.) This data extraction resulted in a total of 205 patients with bladder exstrophy, from a sample of 9,452,110 newborns. To produce national estimates of incidence and other statistics, sampled hospital discharges were weighted according to weight values supplied with the NIS. Since the NIS is a stratified sample of hospitals (stratified by region, location, teaching status, bed size and ownership), these weights are designed to adjust discharges within each stratum to reflect national proportions. Comorbid diagnoses were identified using broad categories based on ICD-9 code prefixes (table 1). Incidence of certain co-morbid diagnoses among newborns with and without exstrophy was compared using chi-square tests, and odds ratios with confidence intervals were calculated. Because the NIS is de-identified, institutional review board approval was not necessary.
TABLE 2. Overall incidence of bladder exstrophy stratified by demographic factors
We identified 205 newborns with bladder exstrophy from the NIS sample of 9,452,110 newborns between 1988 and
RESULTS
Variable
Weighted Incidence (per 100,000)
Race/ethnicity: White Black Hispanic Other Gender: M F Insurance coverage: Self pay Medicaid/other Private/HMO/Medicare SES (median ZIP code income): $1–$24,999 $25,000–$34,999 $35,000–$44,999 $45,000⫹ Geographic region: West Northeast South Midwest Overall incidence Data weighted to general population.
Weighted p Value
TABLE 3. Factors associated with bladder exstrophy in newborns 2.63 1.83 1.33 1.44
⬍0.0001
2.10 2.12
0.8583
1.41 2.23 2.20
0.0224
1.61 2.40 2.98 1.63
⬍0.0001
1.37 2.15 2.49 2.47 2.15
⬍0.0001
Variable
Weighted OR (95% CI)
Race/ethnicity: White 1.0 Black 0.60 (0.46–0.78) Hispanic 0.63 (0.48–0.82) Other 0.63 (0.44–0.89) Insurance coverage: Self pay 1.0 Medicaid/other 1.56 (1.12–2.18) Private/HMO/Medicare 1.34 (0.96–1.86) SES (median ZIP code income): $1–$24,999 1.0 $25,000–$34,999 1.42 (1.19–1.70) $35,000–$44,999 1.82 (1.50–2.21) $45,000⫹ 1.00 (0.79–1.26) Geographic region: West 1.0 Northeast 1.61 (1.30–2.00) South 1.80 (1.49–2.19) Midwest 1.81 (1.47–2.23) Data adjusted for all other significant covariates (multivariate logistic regression) and weighted to national population.
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CONTEMPORARY EPIDEMIOLOGY OF BLADDER EXSTROPHY IN UNITED STATES
2000. This sample results in a weighted national incidence of 2.15 bladder exstrophy cases per 100,000 live births. The incidence of bladder exstrophy appears to be essentially stable, with no significant trend in incidence between 1988 and 2000 (p ⫽ 0.2993). Males and females were affected by exstrophy in roughly equal numbers (table 2). The male-to-female ratio did not differ by race, insurance status or region. Although females were more likely to have infection during hospitalization (16% vs 7%, p ⫽ 0.03), there were otherwise no significant differences in either number of diagnoses or incidence of major congenital anomalies. Females tended to have more jaundice (8% vs 3%, p ⫽ 0.1), gastrointestinal anomalies (26% vs 17%, p ⫽ 0.12) and pulmonary problems (26% vs 15%, p ⫽ 0.05), although the differences were not significant. Females were also more likely to undergo repair of bladder exstrophy during the newborn hospital stay, although again the difference was not significant (21% vs 15%, p ⫽ 0.2). In-hospital deaths were equivalent between males and females (7.8% vs 8.2%, p ⫽ 0.92). There is substantial variation in the incidence of exstrophy by race, with whites significantly more likely to have bladder exstrophy than nonwhites (p ⬍0.0001, table 2). Geographic region also was significantly associated with exstrophy incidence, with the highest incidence in the South and Midwest (table 2). Newborns in the lowest and highest socioeconomic status (SES) strata had lower weighted incidence, while subjects in the middle strata had higher incidence (p ⬍0.0001, table 2). Insurance status was also associated with exstrophy incidence, with subjects without insurance (self pay) having a lower weighted incidence than patients with either Medicaid or private insurance/health maintenance organization (HMO). To adjust for potential confounding by demographic and socioeconomic factors with bladder exstrophy, we performed multivariate analysis (table 3). The associations seen in the bivariate analyses persisted in the multivariate model. The odds of exstrophy in black patients were 40% lower than in white patients (weighted OR 0.60, 95% CI 0.46 to 0.78). Similar associations were seen for other nonwhite groups. There continued to be marked regional variation in incidence even after controlling for racial variation, with the Western region continuing to have a substantially lower incidence of exstrophy than the other regions. SES also had a nonlinear association with exstrophy, with the upper and lower SES levels having significantly lower odds of exstrophy than the middle SES levels. Since major birth defects are often associated with an increased risk of other congenital conditions, we sought to quantify the frequency of some of these conditions. Newborns with exstrophy were more likely to have certain other congenital conditions than newborns without exstrophy (table 1). In particular, preterm birth, gastrointestinal anomalies, spina bifida, orthopedic conditions and cardiovascular anomalies were much more common among the exstrophy population. Newborns with bladder exstrophy also had a higher risk of in-hospital death compared to those without exstrophy (7.34% vs 0.37%, p ⬍0.0001). If we analyze only those newborns who were not transferred to other facilities at discharge (79 newborns with exstrophy, out of 9,309,714 total), the disparity in the death rate is even more pronounced, at 18.5% vs 0.38% (p ⬍0.0001). DISCUSSION
Rare conditions such as bladder exstrophy pose problems for the epidemiological study of disease. Administrative databases such as the NIS provide an opportunity to analyze large cohorts with uniform data collection. We found that bladder exstrophy is present in 2.15 per
100,000 live births in the United States. This finding compares to an estimated incidence of 20.8 per 100,000 live births for spina bifida3 and 100 per 100,000 live births for cleft lip/palate.4 Most estimates of the incidence of bladder exstrophy in the literature are not derived from population based epidemiological studies, but rather from extrapolations from small (mostly surgical) series, and many studies cited in the current literature are surprisingly old.1, 5 In one of the few published population based reports data from 10 different regional birth registries around the world were compiled to estimate bladder exstrophy incidence.6 Incidence in the various registries varied from 2.1 per 100,000 (RhoneAlpes Auvergne, France) to 4.7 per 100,000 (Denmark), for a combined incidence of 3.3 per 100,000. This estimate is lower than those cited in 2 studies from England. In a population based study of malformations in Birmingham in the 1950s Leck et al1 found 9 cases of exstrophy among 190,236 births (4.7 per 100,000), while Rickham5 estimated an incidence of 2.5 to 10 per 100,000 in Liverpool and North Wales between 1941 and 1960, based on surgical cases and without true population based data. Our data differ from all of these reports in that they provide an estimate based on a large, nationally representative sample during a defined period. It may surprise those familiar with the exstrophy literature that equal numbers of male and female newborns carried a diagnosis of bladder exstrophy (table 2). Although most previous case series have shown a male-to-female ratio of 1.7:1 to 3:1, some authors have cited ratios as high as 5:1 or higher.7⫺10 In contrast, epidemiological studies suggest that the male-to-female ratio is closer to 1:1. For example one epidemiological study found a male-to-female ratio of 1.5:1.6 However, another large study found no significant male preponderance among newborns with bladder exstrophy.2 This disparity between the epidemiological and surgical literature is unexplained but intriguing. One is tempted to ascribe it to the inherent selection bias in surgical case series. However, the consistent predominance of males in the surgical literature implies a real biological phenomenon. Are females with exstrophy simply less likely to be surgical candidates? The female newborns in this sample do not appear to have been significantly sicker than the males, so higher co-morbidity alone is probably not enough to explain the dearth of female cases in the surgical literature. We found that white newborns were significantly more likely to have bladder exstrophy than nonwhites. The odds of exstrophy in nonwhite newborns were roughly 40% lower among each of the nonwhite ethnic groups (black, Hispanic, Asian, other) than among whites. The racial differential is present even after adjusting for SES and insurance status, suggesting that the differential may not be due solely to varying access to medical care (table 3). Few previous studies have looked at the association of race with exstrophy. One case-control study examined race as a factor in exstrophy incidence, and although it was found that whites tended to have a higher incidence, the difference was not significant (white-to-nonwhite ratio 1.43:1, 95% CI 0.56 to 3.64).2 Another study demonstrated that newborns of South Asian descent were slightly more likely to have nonhypospadias “genitourinary anomalies” than white Europeans (1.6 vs 1.2 per 1,000, p ⬍0.05) but there was no significant difference in these anomalies between Caribbean blacks and white Europeans.11 This study did not specifically identify cases of bladder exstrophy, and was probably too small (432,778 subjects) to have detected meaningful racial variation in such a rare disorder. One possibility that should be considered with respect to the differences observed in exstrophy incidence is the potential for disparities in termination rates among various population groups or geographic regions. Our study considered only live births. Therefore, if one group (eg Hispanics or Westerners) had a higher rate of pregnancy termination re-
CONTEMPORARY EPIDEMIOLOGY OF BLADDER EXSTROPHY IN UNITED STATES
lated to prenatal diagnosis of exstrophy, it could decrease the number of live births associated with this condition and result in the appearance of a lower actual incidence. However, studies of elective termination do not suggest that nonwhites are more likely to terminate in response to prenatal diagnosis of other conditions such as Down syndrome.12 Furthermore, given the well documented higher rate of prenatal care among whites, this would seem to be an unlikely explanation.13 It is unclear whether such differential termination may underlie the varying incidence by geographic region. Alternatively, geographic variation could be related to differential exposure to environmental teratogens. Our findings regarding associated conditions suggest that children with exstrophy are at increased risk for a number of additional problems (table 1). Although some conditions such as orthopedic or gastrointestinal anomalies might be expected given the nature of the exstrophy defect itself, others such as cleft palate or preterm birth do not appear to be directly related. Their occurrence in far greater numbers than are seen in the nonexstrophy population suggests that global abnormalities in embryogenesis may be present in these patients beyond the evident phenotypic anomalies. However, it is noteworthy that the possible inclusion of newborns with cloacal exstrophy in this sample would inflate the incidence of gastrointestinal anomalies in the exstrophy population to greater than that expected in a group of patients with classic bladder exstrophy. However, since many researchers believe that bladder exstrophy and cloacal exstrophy are related entities on a spectrum of malformation, inclusion of these patients would not be without justification.14, 15 Moreover, as the incidence of cloacal exstrophy is roughly one tenth the incidence of classic bladder exstrophy, most of the sample likely comprises patients with classic bladder exstrophy. Certain limitations inherent in studies of this type need to be considered. First, there are the limitations of using large administrative databases. Our definitions rely on the ICD-9 system, and represent secondary data extracted from the original medical record. Therefore, this method is subject to potentially inaccurate data transfer. Also, there was a relatively high proportion of subjects with missing race/ethnicity data (34.2%). To compensate for the missing data, we applied a separate categorical value for observations with missing race data, allowing their inclusion in the final multivariate model while acknowledging that they did not fit into a defined race category. In addition, ascertainment bias is a concern. While under ascertainment is a concern when dealing with disorders that may be easy to overlook, ascertainment levels have been estimated to be at least 80% for severe malformations such as bladder exstrophy.6, 16 Conversely, patients may have been omitted from this analysis if they were not admitted to the hospital soon after birth, since this database only captures inpatients. CONCLUSIONS
The estimated national incidence of bladder exstrophy among live births in the United States between 1988 and
1731
2000 was 2.15 per 100,000. The incidence among males and females was roughly equal. Bladder exstrophy is significantly more common among white, middle SES and insured patients, and in the non-Western regions of the United States. A number of co-morbid conditions were associated with bladder exstrophy, including cleft palate, spina bifida and preterm birth. The incidence of bladder exstrophy was essentially stable during the study period.
REFERENCES
1. Leck, I., Record, R. G., McKeown, T. and Edwards, J. H.: The incidence of malformations in Birmingham, England, 1950 – 1959. Teratology, 1: 263, 1968 2. Yang, P., Khoury, M. J., Stewart, W. F., Beaty, T. H., Chee, E., Beatty, J. C. et al: Comparative epidemiology of selected midline congenital abnormalities. Genet Epidemiol, 11: 141, 1994 3. Trends in spina bifida and anencephalus in the United States, 1991–1999. Available at: http://www.cdc.gov/nchs/products/ pubs/pubd/hestats/folic/folicfigures.htm. Hyattsville, Maryland: U. S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics. Accessed October 1, 2004 4. Vallino-Napoli, L. D., Riley, M. M. and Halliday, J.: An epidemiologic study of isolated cleft lip, palate, or both in Victoria, Australia from 1983 to 2000. Cleft Palate Craniofac J, 41: 185, 2004 5. Rickham, P. P.: The incidence and treatment of ectopia vesicae. Proc R Soc Med, 54: 389, 1961 6. Epidemiology of bladder exstrophy and epispadias: a communication from the International Clearinghouse for Birth Defects Monitoring Systems. Teratology, 36: 221, 1987 7. Higgins, C. C.: Exstrophy of the bladder: report of 158 cases. Am Surg, 28: 99, 1962 8. Ives, E., Coffey, R. and Carter, C. O.: A family study of bladder exstrophy. J Med Genet, 17: 139, 1980 9. Lattimer, J. K. and Smith, M. J. V.: Exstrophy closure: a followup on 70 cases. J Urol, 95: 356, 1966 10. Grady, R. W., Carr, M. C. and Mitchell, M. E.: Complete primary closure of bladder exstrophy. Epispadias and bladder exstrophy repair. Urol Clin North Am, 26: 95, 1999 11. Leck, I. and Lancashire, R. J.: Birth prevalence of malformations in members of different ethnic groups and in the offspring of matings between them, in Birmingham, England. J Epidemiol Community Health, 49: 171, 1995 12. Kramer, R. L., Jarve, R. K., Yaron, Y., Johnson, M. P., Lampinen, J., Kasperski, S. B. et al: Determinants of parental decisions after the prenatal diagnosis of Down syndrome. Am J Med Genet, 79: 172, 1998 13. Brett, K. M., Schoendorf, K. C. and Kiely, J. L.: Differences between black and white women in the use of prenatal care technologies. Am J Obstet Gynecol, 170: 41, 1994 14. Beaudoin, S., Barbet, P. and Bargy, F.: Pelvic development in the rabbit embryo: implications in the organogenesis of bladder exstrophy. Anat Embryol, 208: 425, 2004 15. Manner, J. and Kluth, D.: A chicken model to study the embryology of cloacal exstrophy. J Pediatr Surg, 38: 678, 2003 16. Kallen, B., Bertollini, R., Castilla, E., Czeizel, A., Knudsen, L. B., Martinez-Frias, M. L. et al: A joint international study on the epidemiology of hypospadias. Acta Paediatr Scand Suppl, 324: 1, 1986
Vol. 173, 1728 –1731, May 2005 Printed in U.S.A.
DOI: 10.1097/01.ju.0000154821.21521.9b
CONTEMPORARY EPIDEMIOLOGY OF BLADDER EXSTROPHY IN THE UNITED STATES CALEB P. NELSON, RODNEY L. DUNN
AND
JOHN T. WEI*
From the Department of Urology, University of Michigan, Ann Arbor, Michigan, and Brady Urological Institute (CPN), Johns Hopkins Hospital, Baltimore, Maryland
ABSTRACT
Purpose: Although bladder exstrophy is much discussed in the urology literature, there are few population based epidemiological data available for this rare condition. The purpose of this study was to use a large nationwide database to collect contemporary data on the incidence and demographics of bladder exstrophy. Materials and Methods: The Healthcare Cost and Utilization Project Nationwide Inpatient Sample is a 20% sample of nonfederal United States hospitals containing data on 5 million to 7 million inpatient stays per year. The sample was limited to newborns, and International Classification of Disease-9 codes were used to identify cases of bladder exstrophy. We then determined nationally weighted incidence through time, and performed multivariate analyses to identify factors associated with exstrophy. Results: We identified 205 patients with exstrophy among 9,452,110 newborns. The overall weighted incidence of exstrophy was 2.15 per 100,000 live births. The male-to-female ratio was almost even (OR 0.989, 95% CI 0.88 to 1.12). White infants were significantly more likely to present with exstrophy than nonwhites (incidence 2.63 vs 1.54 per 100,000, p ⬍0.0001). Exstrophy incidence also varied by geographic region, socioeconomic status (SES) and insurance status. On multivariate analysis the racial variation in exstrophy incidence persisted even after adjustment for geographic region, SES and insurance status. Conditions such as spina bifida, cleft palate, preterm birth and gastrointestinal anomalies were more common in newborns with exstrophy. Conclusions: Bladder exstrophy is rare, occurs in equal numbers of live male and female newborns, and is associated with certain co-morbid conditions. Incidence appears to be stable through time. Nonwhite race, uninsured status, high or low SES and Western geographic region are associated with lower exstrophy incidence. KEY WORDS: bladder exstrophy, epidemiology, demography
Bladder exstrophy remains one of the most challenging conditions managed by pediatric urologists. Although rare, this disorder imposes significant physical, functional, social, sexual and psychological burdens on patients and families. For the health care system the multiple, lengthy and complex operative procedures that patients with exstrophy undergo consume resources disproportionate to the small number of affected individuals. From a reconstructive perspective exstrophy poses unique challenges in the quest to achieve anatomically, functionally and cosmetically satisfactory results. Successive generations of surgeons have taken up the challenge of exstrophy and made great strides in the quest for successful outcomes, yet we remain far from a cure for this condition. One difficulty in the study of rare conditions such as bladder exstrophy is that individual institutions rarely see adequate numbers of patients to draw useful evidence based conclusions. The literature is replete with surgical case series but these are biased by selection and often span decades in time. True population based epidemiological data regarding bladder exstrophy tend to be old1 or regional in scope.2 Hence, contemporary national data are unavailable and little is known regarding demographic characteristics of the affected population. The purpose of this study was to use a nationally repre-
sentative database of inpatient hospitalizations to determine the incidence of and identify demographic factors associated with bladder exstrophy. Secondarily we sought to quantify the frequency of concomitant conditions in newborns with bladder exstrophy. MATERIALS AND METHODS
Nationwide Inpatient Sample (NIS). The NIS is part of the Healthcare Cost and Utilization Project and is the largest all payer inpatient care database that is publicly available in the United States. Each year the NIS provides information on approximately 5 million to 7 million inpatient stays from about 1,000 hospitals, and is designed to approximate a 20% sample of United States nonfederal community hospitals, including specialty hospitals, public hospitals and academic medical centers. Excluded are short-term rehabilitation and long-term, psychiatric and chemical dependency treatment facilities. The data on individual patients include age, diagnosis, procedures and disposition, as well as hospitalization data such as admission type, timing, payer and charges, and information about each hospital that participated in the NIS. Datasets for 1988 through 2000 were merged to create a single dataset containing information on all hospital admissions for this period. Univariate and multivariate analyses were then performed to examine national trends in bladder exstrophy. Epidemiological data analysis. To determine incidence rates of bladder exstrophy, it was necessary to identify new-
Submitted for publication October 25, 2004. * Financial interest and/or other relationship with Sanofi, Laserscope, Calypso and Boehringer Ingelheim. 1728
1729
CONTEMPORARY EPIDEMIOLOGY OF BLADDER EXSTROPHY IN UNITED STATES TABLE 1. Relative weighted incidence of comorbid conditions among newborns with and without exstrophy Weighted Incidence/100 Liveborn Pts With Exstrophy
Comorbid Condition
Weighted Incidence/100 Liveborn Pts Without Exstrophy
OR (95% CI)
Lower gastrointestinal anomalies* 19.3 0.13 188.6 (162–219) Preterm birth† 17.5 6.7 3.0 (2.5–3.5) Orthopedic anomalies‡ 13.2 1.2 13.1 (11.0–15.6) Spina bifida§ 6.8 0.03 224.3 (177–284) Vascular anomalies㛳 4.6 1.1 4.4 (3.3–5.8) Cardiac amomalies¶ 3.4 0.8 4.5 (3.2–6.3) Chromosomal anomalies** 1.1 0.15 7.7 (4.3–13.6) Cleft lip and/or palate†† 1.1 0.13 8.0 (4.4–14.3) * ICD-9 code 751.xx (congenital anomalies of small bowel, eg Meckel’s diverticulum, large bowel, eg Hirschsprung disease, rectum or anus, eg stenosis or imperforate anus). † ICD-9 code 765.0x (extreme immaturity), 765.1x (other preterm newborns), 765.21 to 765.28 (birth before 37 weeks of gestation). ‡ ICD-9 code 754.xx (congenital anomalies of skull, spine, hip, long bones, feet), 755.xx (polydactyly, syndactyly, reduction deformities of limbs). § ICD-9 code 741.xx. 㛳 ICD-9 code 747.xx (eg patent ductus arteriosus, coarctation of aorta). ¶ ICD-9 code 745.xx (eg transposition, tetralogy of Fallot, ventriculoseptal defect), 746.xx (eg cardiac valve anomalies, hypoplastic left heart). ** ICD-9 code 758.xx. †† ICD-9 code 749.xx.
borns. Because the NIS is a database of inpatient discharges, and because patients with bladder exstrophy are transferred between hospitals during the early days of life at a much higher rate than newborns without major congenital anomalies, it is possible that individual patients could appear multiple times in the database, artificially inflating the calculated incidence of exstrophy. To eliminate this concern as much as possible, we used a multistep extraction procedure designed to limit the working dataset to initial newborn hospitalizations. We initially extracted all hospital discharges in which the International Classification of Disease (ICD)-9 diagnosis code V3x.0 (live births in hospital, with or without 1 or more siblings) or V3x.1 (live births before hospitalization, with or without 1 or more siblings) was recorded in 1 of the 15 diagnosis slots. The “before admission” codes (V3x.1x) were included to capture any patients born outside the hospital (eg at home) and then admitted shortly thereafter. Since a small fraction (0.2%) of the patients meeting these criteria were transferred from other health care facilities, we further limited the dataset to those whose “admission source” (variable “asource” in the NIS) was not listed as either “transfer from another acute-care hospital” or “transfer from another
health-care facility.” Finally, we limited these data to patients younger than 2 days at the time of hospitalization. We then identified those patients within this dataset as having bladder exstrophy, based on the presence of ICD-9 code “753.5” in any of the 15 diagnosis slots. (Since there is no discrete ICD-9 code for cloacal exstrophy, it is possible that patients with that diagnosis are included in the sample.) This data extraction resulted in a total of 205 patients with bladder exstrophy, from a sample of 9,452,110 newborns. To produce national estimates of incidence and other statistics, sampled hospital discharges were weighted according to weight values supplied with the NIS. Since the NIS is a stratified sample of hospitals (stratified by region, location, teaching status, bed size and ownership), these weights are designed to adjust discharges within each stratum to reflect national proportions. Comorbid diagnoses were identified using broad categories based on ICD-9 code prefixes (table 1). Incidence of certain co-morbid diagnoses among newborns with and without exstrophy was compared using chi-square tests, and odds ratios with confidence intervals were calculated. Because the NIS is de-identified, institutional review board approval was not necessary.
TABLE 2. Overall incidence of bladder exstrophy stratified by demographic factors
We identified 205 newborns with bladder exstrophy from the NIS sample of 9,452,110 newborns between 1988 and
RESULTS
Variable
Weighted Incidence (per 100,000)
Race/ethnicity: White Black Hispanic Other Gender: M F Insurance coverage: Self pay Medicaid/other Private/HMO/Medicare SES (median ZIP code income): $1–$24,999 $25,000–$34,999 $35,000–$44,999 $45,000⫹ Geographic region: West Northeast South Midwest Overall incidence Data weighted to general population.
Weighted p Value
TABLE 3. Factors associated with bladder exstrophy in newborns 2.63 1.83 1.33 1.44
⬍0.0001
2.10 2.12
0.8583
1.41 2.23 2.20
0.0224
1.61 2.40 2.98 1.63
⬍0.0001
1.37 2.15 2.49 2.47 2.15
⬍0.0001
Variable
Weighted OR (95% CI)
Race/ethnicity: White 1.0 Black 0.60 (0.46–0.78) Hispanic 0.63 (0.48–0.82) Other 0.63 (0.44–0.89) Insurance coverage: Self pay 1.0 Medicaid/other 1.56 (1.12–2.18) Private/HMO/Medicare 1.34 (0.96–1.86) SES (median ZIP code income): $1–$24,999 1.0 $25,000–$34,999 1.42 (1.19–1.70) $35,000–$44,999 1.82 (1.50–2.21) $45,000⫹ 1.00 (0.79–1.26) Geographic region: West 1.0 Northeast 1.61 (1.30–2.00) South 1.80 (1.49–2.19) Midwest 1.81 (1.47–2.23) Data adjusted for all other significant covariates (multivariate logistic regression) and weighted to national population.
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CONTEMPORARY EPIDEMIOLOGY OF BLADDER EXSTROPHY IN UNITED STATES
2000. This sample results in a weighted national incidence of 2.15 bladder exstrophy cases per 100,000 live births. The incidence of bladder exstrophy appears to be essentially stable, with no significant trend in incidence between 1988 and 2000 (p ⫽ 0.2993). Males and females were affected by exstrophy in roughly equal numbers (table 2). The male-to-female ratio did not differ by race, insurance status or region. Although females were more likely to have infection during hospitalization (16% vs 7%, p ⫽ 0.03), there were otherwise no significant differences in either number of diagnoses or incidence of major congenital anomalies. Females tended to have more jaundice (8% vs 3%, p ⫽ 0.1), gastrointestinal anomalies (26% vs 17%, p ⫽ 0.12) and pulmonary problems (26% vs 15%, p ⫽ 0.05), although the differences were not significant. Females were also more likely to undergo repair of bladder exstrophy during the newborn hospital stay, although again the difference was not significant (21% vs 15%, p ⫽ 0.2). In-hospital deaths were equivalent between males and females (7.8% vs 8.2%, p ⫽ 0.92). There is substantial variation in the incidence of exstrophy by race, with whites significantly more likely to have bladder exstrophy than nonwhites (p ⬍0.0001, table 2). Geographic region also was significantly associated with exstrophy incidence, with the highest incidence in the South and Midwest (table 2). Newborns in the lowest and highest socioeconomic status (SES) strata had lower weighted incidence, while subjects in the middle strata had higher incidence (p ⬍0.0001, table 2). Insurance status was also associated with exstrophy incidence, with subjects without insurance (self pay) having a lower weighted incidence than patients with either Medicaid or private insurance/health maintenance organization (HMO). To adjust for potential confounding by demographic and socioeconomic factors with bladder exstrophy, we performed multivariate analysis (table 3). The associations seen in the bivariate analyses persisted in the multivariate model. The odds of exstrophy in black patients were 40% lower than in white patients (weighted OR 0.60, 95% CI 0.46 to 0.78). Similar associations were seen for other nonwhite groups. There continued to be marked regional variation in incidence even after controlling for racial variation, with the Western region continuing to have a substantially lower incidence of exstrophy than the other regions. SES also had a nonlinear association with exstrophy, with the upper and lower SES levels having significantly lower odds of exstrophy than the middle SES levels. Since major birth defects are often associated with an increased risk of other congenital conditions, we sought to quantify the frequency of some of these conditions. Newborns with exstrophy were more likely to have certain other congenital conditions than newborns without exstrophy (table 1). In particular, preterm birth, gastrointestinal anomalies, spina bifida, orthopedic conditions and cardiovascular anomalies were much more common among the exstrophy population. Newborns with bladder exstrophy also had a higher risk of in-hospital death compared to those without exstrophy (7.34% vs 0.37%, p ⬍0.0001). If we analyze only those newborns who were not transferred to other facilities at discharge (79 newborns with exstrophy, out of 9,309,714 total), the disparity in the death rate is even more pronounced, at 18.5% vs 0.38% (p ⬍0.0001). DISCUSSION
Rare conditions such as bladder exstrophy pose problems for the epidemiological study of disease. Administrative databases such as the NIS provide an opportunity to analyze large cohorts with uniform data collection. We found that bladder exstrophy is present in 2.15 per
100,000 live births in the United States. This finding compares to an estimated incidence of 20.8 per 100,000 live births for spina bifida3 and 100 per 100,000 live births for cleft lip/palate.4 Most estimates of the incidence of bladder exstrophy in the literature are not derived from population based epidemiological studies, but rather from extrapolations from small (mostly surgical) series, and many studies cited in the current literature are surprisingly old.1, 5 In one of the few published population based reports data from 10 different regional birth registries around the world were compiled to estimate bladder exstrophy incidence.6 Incidence in the various registries varied from 2.1 per 100,000 (RhoneAlpes Auvergne, France) to 4.7 per 100,000 (Denmark), for a combined incidence of 3.3 per 100,000. This estimate is lower than those cited in 2 studies from England. In a population based study of malformations in Birmingham in the 1950s Leck et al1 found 9 cases of exstrophy among 190,236 births (4.7 per 100,000), while Rickham5 estimated an incidence of 2.5 to 10 per 100,000 in Liverpool and North Wales between 1941 and 1960, based on surgical cases and without true population based data. Our data differ from all of these reports in that they provide an estimate based on a large, nationally representative sample during a defined period. It may surprise those familiar with the exstrophy literature that equal numbers of male and female newborns carried a diagnosis of bladder exstrophy (table 2). Although most previous case series have shown a male-to-female ratio of 1.7:1 to 3:1, some authors have cited ratios as high as 5:1 or higher.7⫺10 In contrast, epidemiological studies suggest that the male-to-female ratio is closer to 1:1. For example one epidemiological study found a male-to-female ratio of 1.5:1.6 However, another large study found no significant male preponderance among newborns with bladder exstrophy.2 This disparity between the epidemiological and surgical literature is unexplained but intriguing. One is tempted to ascribe it to the inherent selection bias in surgical case series. However, the consistent predominance of males in the surgical literature implies a real biological phenomenon. Are females with exstrophy simply less likely to be surgical candidates? The female newborns in this sample do not appear to have been significantly sicker than the males, so higher co-morbidity alone is probably not enough to explain the dearth of female cases in the surgical literature. We found that white newborns were significantly more likely to have bladder exstrophy than nonwhites. The odds of exstrophy in nonwhite newborns were roughly 40% lower among each of the nonwhite ethnic groups (black, Hispanic, Asian, other) than among whites. The racial differential is present even after adjusting for SES and insurance status, suggesting that the differential may not be due solely to varying access to medical care (table 3). Few previous studies have looked at the association of race with exstrophy. One case-control study examined race as a factor in exstrophy incidence, and although it was found that whites tended to have a higher incidence, the difference was not significant (white-to-nonwhite ratio 1.43:1, 95% CI 0.56 to 3.64).2 Another study demonstrated that newborns of South Asian descent were slightly more likely to have nonhypospadias “genitourinary anomalies” than white Europeans (1.6 vs 1.2 per 1,000, p ⬍0.05) but there was no significant difference in these anomalies between Caribbean blacks and white Europeans.11 This study did not specifically identify cases of bladder exstrophy, and was probably too small (432,778 subjects) to have detected meaningful racial variation in such a rare disorder. One possibility that should be considered with respect to the differences observed in exstrophy incidence is the potential for disparities in termination rates among various population groups or geographic regions. Our study considered only live births. Therefore, if one group (eg Hispanics or Westerners) had a higher rate of pregnancy termination re-
CONTEMPORARY EPIDEMIOLOGY OF BLADDER EXSTROPHY IN UNITED STATES
lated to prenatal diagnosis of exstrophy, it could decrease the number of live births associated with this condition and result in the appearance of a lower actual incidence. However, studies of elective termination do not suggest that nonwhites are more likely to terminate in response to prenatal diagnosis of other conditions such as Down syndrome.12 Furthermore, given the well documented higher rate of prenatal care among whites, this would seem to be an unlikely explanation.13 It is unclear whether such differential termination may underlie the varying incidence by geographic region. Alternatively, geographic variation could be related to differential exposure to environmental teratogens. Our findings regarding associated conditions suggest that children with exstrophy are at increased risk for a number of additional problems (table 1). Although some conditions such as orthopedic or gastrointestinal anomalies might be expected given the nature of the exstrophy defect itself, others such as cleft palate or preterm birth do not appear to be directly related. Their occurrence in far greater numbers than are seen in the nonexstrophy population suggests that global abnormalities in embryogenesis may be present in these patients beyond the evident phenotypic anomalies. However, it is noteworthy that the possible inclusion of newborns with cloacal exstrophy in this sample would inflate the incidence of gastrointestinal anomalies in the exstrophy population to greater than that expected in a group of patients with classic bladder exstrophy. However, since many researchers believe that bladder exstrophy and cloacal exstrophy are related entities on a spectrum of malformation, inclusion of these patients would not be without justification.14, 15 Moreover, as the incidence of cloacal exstrophy is roughly one tenth the incidence of classic bladder exstrophy, most of the sample likely comprises patients with classic bladder exstrophy. Certain limitations inherent in studies of this type need to be considered. First, there are the limitations of using large administrative databases. Our definitions rely on the ICD-9 system, and represent secondary data extracted from the original medical record. Therefore, this method is subject to potentially inaccurate data transfer. Also, there was a relatively high proportion of subjects with missing race/ethnicity data (34.2%). To compensate for the missing data, we applied a separate categorical value for observations with missing race data, allowing their inclusion in the final multivariate model while acknowledging that they did not fit into a defined race category. In addition, ascertainment bias is a concern. While under ascertainment is a concern when dealing with disorders that may be easy to overlook, ascertainment levels have been estimated to be at least 80% for severe malformations such as bladder exstrophy.6, 16 Conversely, patients may have been omitted from this analysis if they were not admitted to the hospital soon after birth, since this database only captures inpatients. CONCLUSIONS
The estimated national incidence of bladder exstrophy among live births in the United States between 1988 and
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2000 was 2.15 per 100,000. The incidence among males and females was roughly equal. Bladder exstrophy is significantly more common among white, middle SES and insured patients, and in the non-Western regions of the United States. A number of co-morbid conditions were associated with bladder exstrophy, including cleft palate, spina bifida and preterm birth. The incidence of bladder exstrophy was essentially stable during the study period.
REFERENCES
1. Leck, I., Record, R. G., McKeown, T. and Edwards, J. H.: The incidence of malformations in Birmingham, England, 1950 – 1959. Teratology, 1: 263, 1968 2. Yang, P., Khoury, M. J., Stewart, W. F., Beaty, T. H., Chee, E., Beatty, J. C. et al: Comparative epidemiology of selected midline congenital abnormalities. Genet Epidemiol, 11: 141, 1994 3. Trends in spina bifida and anencephalus in the United States, 1991–1999. Available at: http://www.cdc.gov/nchs/products/ pubs/pubd/hestats/folic/folicfigures.htm. Hyattsville, Maryland: U. S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics. Accessed October 1, 2004 4. Vallino-Napoli, L. D., Riley, M. M. and Halliday, J.: An epidemiologic study of isolated cleft lip, palate, or both in Victoria, Australia from 1983 to 2000. Cleft Palate Craniofac J, 41: 185, 2004 5. Rickham, P. P.: The incidence and treatment of ectopia vesicae. Proc R Soc Med, 54: 389, 1961 6. Epidemiology of bladder exstrophy and epispadias: a communication from the International Clearinghouse for Birth Defects Monitoring Systems. Teratology, 36: 221, 1987 7. Higgins, C. C.: Exstrophy of the bladder: report of 158 cases. Am Surg, 28: 99, 1962 8. Ives, E., Coffey, R. and Carter, C. O.: A family study of bladder exstrophy. J Med Genet, 17: 139, 1980 9. Lattimer, J. K. and Smith, M. J. V.: Exstrophy closure: a followup on 70 cases. J Urol, 95: 356, 1966 10. Grady, R. W., Carr, M. C. and Mitchell, M. E.: Complete primary closure of bladder exstrophy. Epispadias and bladder exstrophy repair. Urol Clin North Am, 26: 95, 1999 11. Leck, I. and Lancashire, R. J.: Birth prevalence of malformations in members of different ethnic groups and in the offspring of matings between them, in Birmingham, England. J Epidemiol Community Health, 49: 171, 1995 12. Kramer, R. L., Jarve, R. K., Yaron, Y., Johnson, M. P., Lampinen, J., Kasperski, S. B. et al: Determinants of parental decisions after the prenatal diagnosis of Down syndrome. Am J Med Genet, 79: 172, 1998 13. Brett, K. M., Schoendorf, K. C. and Kiely, J. L.: Differences between black and white women in the use of prenatal care technologies. Am J Obstet Gynecol, 170: 41, 1994 14. Beaudoin, S., Barbet, P. and Bargy, F.: Pelvic development in the rabbit embryo: implications in the organogenesis of bladder exstrophy. Anat Embryol, 208: 425, 2004 15. Manner, J. and Kluth, D.: A chicken model to study the embryology of cloacal exstrophy. J Pediatr Surg, 38: 678, 2003 16. Kallen, B., Bertollini, R., Castilla, E., Czeizel, A., Knudsen, L. B., Martinez-Frias, M. L. et al: A joint international study on the epidemiology of hypospadias. Acta Paediatr Scand Suppl, 324: 1, 1986