- Email: [email protected]
Incidence of Biliary Atresia and Timing of Hepatoportoenterostomy in the United States
ARTICLE IN PRESS THE JOURNAL OF PEDIATRICS • www.jpeds.com
ORIGINAL ARTICLES
Incidence of Biliary Atresia and Timing of Hepatoportoenterostomy in the United States Perri C. Hopkins, MD1, Nada Yazigi, MD2, and Cade M. Nylund, MD1 Objective To evaluate the incidence, trends, seasonality, and age at the time of hepatoportoenterostomy (Kasai procedure) for biliary atresia in the US. Study design The triennial Health Cost and Utilization Project–Kids’ Inpatient Database for 1997-2012 was used to perform a retrospective analysis of biliary atresia in the US. Infants aged <1 year of age with a diagnosis of biliary atresia who underwent a Kasai procedure were included. Nationwide infant population data were used to calculate incidence and evaluate trends. Age at the time of the Kasai procedure and the seasonality of biliary atresia were evaluated as well. Results The incidence of biliary atresia in the US was 4.47 per 100 000 and was higher in females (risk ratio [RR], 1.43; 95% CI, 1.27-1.62), Asian/Pacific Islanders (RR, 1.89; 95% CI, 1.44-2.47), and blacks (RR, 1.30; 95% CI, 1.06-1.58) compared with whites. The incidence of biliary atresia increased by an average of 7.9% per year from 1997 to 2012 (P < .001). The median age at the time of the Kasai procedure was 63 days, with no improvement over the study period (P = .64). There was no evidence of seasonality (P = .69). Conclusion The incidence of biliary atresia has increased over the past 15 years, with the median age at the time of the Kasai procedure now outside the optimal window. Implementation of systematic screening measures for biliary atresia in the US are needed. (J Pediatr 2017;■■:■■-■■).
B
iliary atresia is a progressive destructive disorder of the intrahepatic and extrahepatic bile ducts. Left untreated, biliary atresia is fatal, making it the leading indication for liver transplantation in children.1 There is no medical treatment for biliary atresia; surgical treatment with hepatoportoenterostomy (Kasai procedure) is the gold standard.2,3 Successful establishment of bile flow with the Kasai procedure is directly linked to an increase in patient survival with native liver.4 Among infants who undergo the Kasai procedure within 60 days of life, 57%-90% will have successful reestablishment of bile flow, but the success rate drops to <20% if the procedure is performed after 90 days of life.2,5-7 This time-sensitive success rate makes the infant’s age at the time of surgery crucial to optimize outcomes and decrease short- and long-term morbidity and mortality,2,3 and underscores the importance of early diagnosis of biliary atresia. The pathogenesis of biliary atresia is not well understood, but owing to a reported seasonality of the disease in some population studies, is thought to be linked to a viral illness that stimulates the inflammatory obliteration of the bile ducts. Studies using a rotavirus-induced murine model of biliary atresia have shown that maternal vaccination against rotavirus can prevent biliary atresia in newborn mouse pups.8,9 Lin et al found a significant drop in the incidence of biliary atresia in Taiwan between 2004-2006 and 2007-2009 (1.76 cases vs 1.23 cases per 10 000 live births).10 The trend toward decreasing biliary atresia in Taiwan is hypothesized to be linked to implementation of a nationwide rotavirus vaccination.10 The impact, if any, of rotavirus vaccination on the incidence of biliary atresia in the US is unclear. The American Academy of Pediatrics (AAP) technical report on newborn screening for biliary atresia noted that the incidence and prevalence of biliary atresia are current key questions.11 We conducted the present study to determine the incidence of biliary atresia in the US, and to evaluate whether that incidence is decreasing, similar to what has been seen in other countries. Secondary aims were to determine whether early From the 1Department of Pediatrics, Uniformed Services identification of biliary atresia is improving in the US, resulting in performance University of the Health Sciences, Bethesda, MD; and 2MedStar Georgetown Transplant Institute, Washington, of the Kasai procedure during the optimal window of the first 60 days of life, and DC to evaluate whether there is seasonality to the incidence of biliary atresia in the This work was prepared as part of the official duties of US. C.N. and P.H., who are employed by the US Air Force. The views expressed in this article are those of the authors, and do not reflect the official policy or position of the US Air Force, US Department of Defense, or US Government. The authors declare no conflict of interest.
AAP HCUP-KID ICD-9 RR
American Academy of Pediatrics Healthcare Cost and Utilization Project-Kids’ Inpatient Database International Statistical Classification of Diseases and Related Health Problems, Ninth Revision Risk ratio
Portions of this study were presented as an abstract during the American Academy of Pediatrics National Conference and Exhibition Poster Presentation, Uniformed Services Section, San Diego, CA, October 11-14, 2014. 0022-3476/$ - see front matter. Published by Elsevier Inc. http://dx.doi.org10.1016/j.jpeds.2017.05.006
1 FLA 5.4.0 DTD ■ YMPD9184_proof ■ June 1, 2017
THE JOURNAL OF PEDIATRICS • www.jpeds.com Methods Data on biliary atresia hospitalizations in children aged <1 year were obtained from the triennial Healthcare Cost and Utilization Project–Kids’ Inpatient Database (HCUP-KID), sponsored by the Agency for Healthcare Research and Quality. The HCUP-KID is the largest publicly available nationwide inpatient database devoted to children in the US. National total population data by age and year also are available from the HCUP-KID, to allow estimates of incidence. The database used for the present study consisted of a stratified random sample across 6 years: 1997, 2000, 2003, 2006, 2009, and 2012. It contains approximately 3 million pediatric inpatient records per year from 4100 hospitals collected between 1997 and 2012. The database includes data from between 22 and 44 states, depending on the year. Each record in the database includes up to 25 diagnoses (15 before 2009) and 15 procedural codes based on the International Statistical Classification of Diseases and Related Health Problems, Ninth Revision (ICD-9). The HCUPKID assigns an individual-level population weight that allows for estimation of national case incidences and trends. The age in days at time of admission is reported for infants aged <1 year between 1997 and 2009.12 Variable Definition Case selection was performed by searching the database for children aged <1 year with the ICD-9 diagnostic code for biliary atresia (751.61) and for the procedure code for the Kasai hepatoportoenterostomy procedure (51.37). Criteria for inclusion in the study were the diagnosis code for biliary atresia and receipt of the Kasai hepatoportoenterostomy during hospitalization. In an effort to identify only incident cases of biliary atresia and to avoid duplicating subjects in the database, subjects identified as having undergone liver transplantation during hospitalization (50.5X, 998.1) were excluded. The population denominator data by year were obtained from the HCUP-KID.13 Demographic data included race, sex, and geographic region. The analysis of race/ethnicity was grouped into white, black, Hispanic, Asian/Pacific Islander, Native American, and other, based on race classification provided in the HCUP-KID. The hospital region was classified as Northeast, Midwest, South, or West. Statistical Analyses The overall and yearly incidences of biliary atresia were calculated by dividing the nationally weighted number of hospital admissions that met the study criteria by the total number of reported infants in the US population for the respective years. The estimated population of infants (ie, children aged <1 year) is reported by the HCUP-KID.14 The trends in biliary atresia were tested using the Cochrane-Armitage test of trend. Patient age at the time of Kasai hepatoportoenterostomy was calculated using age in days at the time of admission to the hospital as reported by the HCUP-KID. The age in days data represented only a subset of subjects, because available data were limited to the years 1997-2009. The age distribution at the time of Kasai hepatoportoenterostomy was found to be
Volume ■■ skewed and is reported as median (IQR). The Kruskal-Wallis test was used to test differences in age at the time of Kasai hepatoportoenterostomy across the years. The seasonality of biliary atresia was tested using the X11 procedure, an adaptation of the US Census Bureau’s X-11 Seasonal Adjustment program.15,16 A combination of 2 tests of seasonality—the stable seasonality test and moving seasonality test—was used. The stable seasonality test is a 1-way ANOVA on the detrended series with months as the factor. The moving seasonality test is a 2-way analysis that uses both months and years.15 The analyses were performed using the provided population weights as recommended by HCUP-KID documentation.12 Statistical analyses were performed using SAS version 9.3 (SAS Institute, Cary, North Carolina), and all statistical tests were performed at a significance level of a = 0.05. This study was reviewed and approved by the Uniformed Services University of the Health Sciences Institutional Review Board.
Results A total of 1057 nationally weighted cases of biliary atresia recorded in the US between 1997 and 2012 met the study cirteria. The overall incidence of biliary atresia in the US in 19972012 was 4.47 per 100 000 children age <1 year. The incidence of biliary atresia was higher in females than in males (5.36 per 100 000 vs 3.74 per 100 000; risk ratio [RR], 1.43; 95% CI, 1.27-1.62) (Table). Asian/Pacific Islanders had a higher incidence of biliary atresia compared with whites (7.55 per 100 000 vs 4.00 per 100 000; RR, 1.89; 95% CI, 1.442.47) or with blacks (5.18 per 100 000; RR, 1.30; 95% CI, 1.061.58). There was no significant difference in the incidence of biliary atresia across US regions (P = .29). The incidence of biliary atresia increased significantly over the study period, from 2.85 cases per 100 000 in 1997 to 5.55
Table. Demographics of biliary atresia in the US, 1997-2012
Variables Sex Female Male Race White Black Hispanic Asian/Pacific Islander Native American Other Unreported race Region Northeast Midwest South West
2
No. of biliary atresia cases
Incidence per 100 000 children
RR (95% CI)
610 446
5.36 3.74
1.43 (1.27-1.62) Reference
403 131 174 612 2 79 207
4.00 5.18 4.43 7.55 1.67 7.72 4.25
Reference 1.30 (1.06-1.58) 1.11 (0.93-1.32) 1.89 (1.44-2.47) 0.42 (0.10-1.67) 1.93 (1.52-2.46)
192 245 365 255
4.85 4.80 4.20 4.56
P value <.001 <.001 <.001 .26 <.001 .22 <.001 .29
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Figure 3. Number of biliary atresia cases per month in the US, demonstrating a lack of seasonality. Figure 1. Incidence of biliary atresia per 100 000 infants in the US, 1997-2012.
cases per 100 000 in 2012 (P < .001), an average annual percent increase of 7.9% (Figure 1). The overall median age at the time of Kasai hepatoportoenterostomy was 63 days (IQR, 47-76 days), and there was no significant change in age at the time of the Kasai procedure between 1997 and 2009 (P = .64) (Figure 2). When the cases of biliary atresia were separated by month, there was insufficient evidence of seasonality in the incidence of biliary atresia (P = .69) (Figure 3).
Discussion In published literature, the reported incidence of biliary atresia in the US ranges from 1 in 10 000 to 1 in 18 000 live births.17 A previous study in Atlanta, Georgia reported an incidence of biliary atresia of 1 in 14 000 between 1968 and 1993.18 A study done in New York reported an incidence of 1 in 11 800 live births in 1983-1998.17 Our study calculated a lower nationwide incidence of 1 in 22 371 infants between 1997 and 2012. This suggests that the overall incidence may have decreased since the 1970s. It also is possible that because our study relied on billing data, the incidence may be underrepresented owing to misclassification bias. This difference may represent a geo-
Figure 2. Median (IQR) age at the time of the Kasai hepatoportoenterostomy procedure in the US, 1997-2009.
graphical variation in biliary atresia, given that these studies were limited to 1 geographical area within the US. In the present study, however, there were no significant differences in the incidence of biliary atresia among the 4 main regions of the US as classified by the HCUP-KID. We found that the incidence of biliary atresia varied by sex and race. Female infants were at increased risk for biliary atresia compared with their male counterparts (RR, 1.43) (Table). Consistent with previous reports, we found that the incidence of biliary atresia varied by race. Compared with whites, Asian/ Pacific Islanders and blacks were at increased risk for biliary atresia, with 0.75 cases per 10 000 (RR, 1.89) and 0.52 cases per 10 000 (RR, 1.30), respectively (Table).10,18 The incidence of biliary atresia rose significantly during the study period, with the number of cases almost doubling from 1997 to 2012. This contrasts with the overall decreased incidence of biliary atresia reported in Taiwan from 2004 to 2009.10 Lin et al10 suggested a possible population-level natural cycle and fluctuation of biliary atresia. This hypothesis could explain the fluctuation that we noted in the US, with a higher incidence of biliary atresia from the 1970s to the early 1990s,17-19 followed by a lower incidence from the mid-1990s to the 2000s, and then a rise thereafter (Figure 1). Along with diagnostic bias, other factors contributing to this fluctuation could include racial and ethnic population changes, as well as environmental factors during pregnancy or the perinatal period. Viral infections have long been suspected to cause biliary atresia, specifically rotavirus, as studied in the murine model, which demonstrated that maternal rotavirus vaccination protected against rotavirus-induced murine biliary atresia.8 Lin et al theorized that the decreased incidence of biliary atresia could be due to the nationwide implementation of rotavirus vaccination in 2006.10 Even though rotavirus vaccination is usually administered after age 2 months, they postulated that herd immunity plays a role in protecting against biliary atresia during pregnancy or in the perinatal period, although the negative correlation of biliary atresia and vaccination rate was not significant (P = .07).10 Following implementation of the rotavirus vaccination program in 2006, rotavirus activity in the US declined dramatically, 20 although the incidence of biliary atresia
Incidence of Biliary Atresia and Timing of Hepatoportoenterostomy in the United States FLA 5.4.0 DTD ■ YMPD9184_proof ■ June 1, 2017
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THE JOURNAL OF PEDIATRICS • www.jpeds.com increased (Figure 1). Rotavirus infections typically occur during the winter months in temperate regions.21 Europe and North America had a prevalence of rotavirus of 37%-60% during the peak winter months and of 4%-11% in the summer months.22 A systematic review assessing the evidence for seasonal variation of biliary atresia worldwide found inconclusive data.23 In the present study, we found no significant seasonality of biliary atresia in the US (Figure 3). The lack of seasonality, together with a trend toward an increased prevalence of biliary atresia during the period of rotavirus vaccine implementation, suggests that rotavirus might not be associated with the development of biliary atresia. A caveat of this study is that implementation of a rotavirus vaccination program during the study period might have limited our ability to identify statistically significant seasonality possibly due to rotavirus. In our study, we found that >50% of all children with biliary atresia in the US underwent the Kasai procedure outside of the optimal window of 60 days of life, with a median age of 63 days (IQR, 47-76 days). In addition, patient age at the time of the Kasai procedure has remained stable from 1997 to 2009, suggesting that early identification of biliary atresia has not improved in the US (Figure 2). Because early diagnosis and the Kasai procedure are associated with greater survival of both the infant and his or her native liver, early detection of biliary atresia is important to allow performance of the Kasai procedure within the optimal window. The AAP’s technical report on newborn screening for biliary atresia underscores the importance of early identification of biliary atresia and discusses the feasibility of various biliary atresia screening methods for improving outcomes.11 One screening program involves the distribution of stool color cards with pictures of normal and abnormal stools, including claycolored, to parents to encourage them to seek prompt treatment for their infants with abnormal stools. Taiwan implemented a stool card screening program in 2002 and found that this program was associated with a significant increase in the number of early Kasai procedures, with 90% of cases diagnosed before 60 days of life.24 Mogul et al25 used a Markov model to determine that stool color card screening can be an economically feasible strategy to improve future biliary atresia outcomes in the US, with 30 life-years gained, 11 fewer liver transplants, 3 fewer deaths, and a $9 million decrease in total costs. Another, more objective screening method is to measure serum-conjugated or direct-reacting bilirubin concentrations as an early indicator of biliary atresia. Harpavat et al26 found that all infants with biliary atresia had elevated direct bilirubin/conjugated bilirubin as newborns, starting as early as 1 hour of life despite a normal total serum bilirubin level. These findings suggest that biliary atresia potentially can be identified before clinically significant liver injury occurs. These 2 screening methods, stool color card and direct bilirubin/conjugated bilirubin level, have the potential to significantly decrease the age at which Kasai hepatoportoenterostomy is performed. According to the AAP’s technical report, both stool color cards and conjugated bilirubin concentration have clinical validity as a potential screen-
Volume ■■ ing method for biliary atresia, with no significant clinical risk or harm to the infant. Further studies are warranted to determine the feasibility, effectiveness, and costs of these screening tools.11 Our definition of biliary atresia was based on ICD-9 coding. As in all studies using diagnostic codes, there is concern about possible misclassification and reporting bias, which could have led to a falsely low reported incidence of biliary atresia in this study. We attempted to minimize this bias by using diagnostic codes for both biliary atresia and Kasai hepatoportoenterostomy. Our study did not capture the rare patients with biliary atresia identified after age 1 year or those who were poor candidates for Kasai hepatoportoenterostomy and went directly to liver transplantation. This adds to the potential bias contributing to underestimation of the incidence of biliary atresia in the US. The identified trend toward an increasing prevalence of biliary atresia possibly can be explained by better identification of infants with biliary atresia. A major strength of our study is that the HCUP-KID provides an excellent national representative sample of pediatric hospitalizations rather than just a sample from a specific region, allowing us to examine the epidemiology of biliary atresia across the US. The HCUP-KID, the largest inpatient pediatric database in the US, provides robust national estimates of hospitalized diseases; nonetheless, sampling bias might have impacted our calculated estimates of biliary atresia. According to the HCUP-KID documentation in 2012, the database captured a representative sample of 95.6% of pediatric hospitalizations in the US.12 The HCUP-KID does not include all inpatient records, but does include records from all types of hospitals. Although the HCUP-KID–provided weights account for the poststratification sampling design of the database, Kasai hepatoportoenterostomies likely would be performed more often at children’s hospitals, thus potentially introducing sampling bias. ■ Submitted for publication Oct 21, 2016; last revision received Apr 10, 2017; accepted May 2, 2017 Reprint requests: Perri Hopkins, MD, San Antonio Military Medical Center, Pediatric Residency Program, 3551 Roger Brooke Dr, JBSA Fort Sam Houston, TX 78234. E-mail: [email protected].
References 1. Suchy FJ, Burdelski M, Tomar BS, Sokol RJ. Cholestatic liver disease: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr 2002;35(Suppl 2):S89-97. 2. Nio M, Ohi R, Miyano T, Saeki M, Shiraki K, Tanaka K, et al. Five- and 10-year survival rates after surgery for biliary atresia: a report from the Japanese Biliary Atresia Registry. J Pediatr Surg 2003;38:9971000. 3. Ohi R. Surgery for biliary atresia. Liver 2001;21:175-82. 4. Shneider BL, Brown MB, Haber B, Whitington PF, Schwarz K, Squires R, et al. A multicenter study of the outcome of biliary atresia in the United States, 1997 to 2000. J Pediatr 2006;148:467-74. 5. Suchy FJ. Neonatal cholestasis. Pediatr Rev 2004;25:388-96. 6. Serinet MO, Wildhaber BE, Broué P, Lachaux A, Sarles J, Jacquemin E, et al. Impact of age at Kasai operation on its results in late childhood and adolescence: a rational basis for biliary atresia screening. Pediatrics 2009;123:1280-6.
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7. Mieli-Vergani G, Howard ER, Portman B, Mowat AP. Late referral for biliary atresia–missed opportunities for effective surgery. Lancet 1989;1:4213. 8. Turowski C, Leonhardt J, Teichmann B, Heim A, Baumann U, Kuebler JF, et al. Preconceptional oral vaccination prevents experimental biliary atresia in newborn mice. Eur J Pediatr Surg 2010;20:158-63. 9. Bondoc AJ, Jafri MA, Donnelly B, Mohanty SK, McNeal MM, Ward RL, et al. Prevention of the murine model of biliary atresia after live rotavirus vaccination of dams. J Pediatr Surg 2009;44:1479-90. 10. Lin YC, Chang MH, Liao SF, Wu JF, Ni YH, Tiao MM, et al. Decreasing rate of biliary atresia in Taiwan: a survey, 2004-2009. Pediatrics 2011;128:e530-6. 11. Wang KS. Newborn screening for biliary atresia. Pediatrics 2015;136:e16639. 12. Healthcare Cost and Utilization Project (HCUP). Overview of the Kids’ Inpatient Database (KID), 2012. Available at: http://www.hcup-us.ahrq.gov/ kidoverview.jsp. Accessed November 1, 2015. 13. Barrett M, Lopez-Gonzalez L, Coffey R, Levit K. Population denominator data for use with the HCUP databases (updated with 2012 population data). Available at: http://www.hcup-us.ahrq.gov/reports/methods/ 2013_01.pdf. Accessed March 8, 2013. 14. Barrett M, Hickey K, Coffey R, Levit K. Population denominator data for use with the HCUP databases (updated with 2014 population data). Available at: http://www.hcup-us.ahrq.gov/reports/methods/2015-07.pdf. Accessed September 1, 2015. 15. SAS Institute Inc. 2014 SAS/ETS 13.2 user’s guide: high-performance procedures. Cary, NC: SAS Institute Inc.. 16. Bell WR, Hillmer SC. Issues involved with the seasonal adjustment of economic time series. J Bus Econ Stat 1984;2:291-320.
17. Caton AR, Druschel CM, McNutt LA. The epidemiology of extrahepatic biliary atresia in New York State, 1983-98. Paediatr Perinat Epidemiol 2004;18:97-105. 18. Yoon PW, Bresee JS, Olney RS, James LM, Khoury MJ. Epidemiology of biliary atresia: a population-based study. Pediatrics 1997;99:376-82. 19. Sokol RJ, Mack C, Narkewicz MR, Karrer FM. Pathogenesis and outcome of biliary atresia: current concepts. J Pediatr Gastroenterol Nutr 2003;37:421. 20. Tate JE, Mutuc JD, Panozzo CA, Payne DC, Cortese MM, Cortes JE, et al. Sustained decline in rotavirus detections in the United States following the introduction of rotavirus vaccine in 2006. Pediatr Infect Dis J 2011;30(1 Suppl):S30-4. 21. Cook SM, Glass RI, LeBaron CW, Ho MS. Global seasonality of rotavirus infections. Bull World Health Organ 1990;68:171-7. 22. Patel MM, Pitzer VE, Alonso WJ, Vera D, Lopman B, Tate J, et al. Global seasonality of rotavirus disease. Pediatr Infect Dis J 2013;32:e13447. 23. Jimenez-Rivera C, Jolin-Dahel KS, Fortinsky KJ, Gozdyra P, Benchimol EI. International incidence and outcomes of biliary atresia. J Pediatr Gastroenterol Nutr 2013;56:344-54. 24. Lien TH, Chang MH, Wu JF, Chen HL, Lee HC, Chen AC, et al. Effects of the infant stool color card screening program on 5-year outcome of biliary atresia in Taiwan. Hepatology 2011;53:202-8. 25. Mogul D, Zhou M, Intihar P, Schwarz K, Frick K. Cost-effective analysis of screening for biliary atresia with the stool color card. J Pediatr Gastroenterol Nutr 2015;60:91-8. 26. Harpavat S, Finegold MJ, Karpen SJ. Patients with biliary atresia have elevated direct/conjugated bilirubin levels shortly after birth. Pediatrics 2011;128:e1428-33.
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ORIGINAL ARTICLES
Incidence of Biliary Atresia and Timing of Hepatoportoenterostomy in the United States Perri C. Hopkins, MD1, Nada Yazigi, MD2, and Cade M. Nylund, MD1 Objective To evaluate the incidence, trends, seasonality, and age at the time of hepatoportoenterostomy (Kasai procedure) for biliary atresia in the US. Study design The triennial Health Cost and Utilization Project–Kids’ Inpatient Database for 1997-2012 was used to perform a retrospective analysis of biliary atresia in the US. Infants aged <1 year of age with a diagnosis of biliary atresia who underwent a Kasai procedure were included. Nationwide infant population data were used to calculate incidence and evaluate trends. Age at the time of the Kasai procedure and the seasonality of biliary atresia were evaluated as well. Results The incidence of biliary atresia in the US was 4.47 per 100 000 and was higher in females (risk ratio [RR], 1.43; 95% CI, 1.27-1.62), Asian/Pacific Islanders (RR, 1.89; 95% CI, 1.44-2.47), and blacks (RR, 1.30; 95% CI, 1.06-1.58) compared with whites. The incidence of biliary atresia increased by an average of 7.9% per year from 1997 to 2012 (P < .001). The median age at the time of the Kasai procedure was 63 days, with no improvement over the study period (P = .64). There was no evidence of seasonality (P = .69). Conclusion The incidence of biliary atresia has increased over the past 15 years, with the median age at the time of the Kasai procedure now outside the optimal window. Implementation of systematic screening measures for biliary atresia in the US are needed. (J Pediatr 2017;■■:■■-■■).
B
iliary atresia is a progressive destructive disorder of the intrahepatic and extrahepatic bile ducts. Left untreated, biliary atresia is fatal, making it the leading indication for liver transplantation in children.1 There is no medical treatment for biliary atresia; surgical treatment with hepatoportoenterostomy (Kasai procedure) is the gold standard.2,3 Successful establishment of bile flow with the Kasai procedure is directly linked to an increase in patient survival with native liver.4 Among infants who undergo the Kasai procedure within 60 days of life, 57%-90% will have successful reestablishment of bile flow, but the success rate drops to <20% if the procedure is performed after 90 days of life.2,5-7 This time-sensitive success rate makes the infant’s age at the time of surgery crucial to optimize outcomes and decrease short- and long-term morbidity and mortality,2,3 and underscores the importance of early diagnosis of biliary atresia. The pathogenesis of biliary atresia is not well understood, but owing to a reported seasonality of the disease in some population studies, is thought to be linked to a viral illness that stimulates the inflammatory obliteration of the bile ducts. Studies using a rotavirus-induced murine model of biliary atresia have shown that maternal vaccination against rotavirus can prevent biliary atresia in newborn mouse pups.8,9 Lin et al found a significant drop in the incidence of biliary atresia in Taiwan between 2004-2006 and 2007-2009 (1.76 cases vs 1.23 cases per 10 000 live births).10 The trend toward decreasing biliary atresia in Taiwan is hypothesized to be linked to implementation of a nationwide rotavirus vaccination.10 The impact, if any, of rotavirus vaccination on the incidence of biliary atresia in the US is unclear. The American Academy of Pediatrics (AAP) technical report on newborn screening for biliary atresia noted that the incidence and prevalence of biliary atresia are current key questions.11 We conducted the present study to determine the incidence of biliary atresia in the US, and to evaluate whether that incidence is decreasing, similar to what has been seen in other countries. Secondary aims were to determine whether early From the 1Department of Pediatrics, Uniformed Services identification of biliary atresia is improving in the US, resulting in performance University of the Health Sciences, Bethesda, MD; and 2MedStar Georgetown Transplant Institute, Washington, of the Kasai procedure during the optimal window of the first 60 days of life, and DC to evaluate whether there is seasonality to the incidence of biliary atresia in the This work was prepared as part of the official duties of US. C.N. and P.H., who are employed by the US Air Force. The views expressed in this article are those of the authors, and do not reflect the official policy or position of the US Air Force, US Department of Defense, or US Government. The authors declare no conflict of interest.
AAP HCUP-KID ICD-9 RR
American Academy of Pediatrics Healthcare Cost and Utilization Project-Kids’ Inpatient Database International Statistical Classification of Diseases and Related Health Problems, Ninth Revision Risk ratio
Portions of this study were presented as an abstract during the American Academy of Pediatrics National Conference and Exhibition Poster Presentation, Uniformed Services Section, San Diego, CA, October 11-14, 2014. 0022-3476/$ - see front matter. Published by Elsevier Inc. http://dx.doi.org10.1016/j.jpeds.2017.05.006
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THE JOURNAL OF PEDIATRICS • www.jpeds.com Methods Data on biliary atresia hospitalizations in children aged <1 year were obtained from the triennial Healthcare Cost and Utilization Project–Kids’ Inpatient Database (HCUP-KID), sponsored by the Agency for Healthcare Research and Quality. The HCUP-KID is the largest publicly available nationwide inpatient database devoted to children in the US. National total population data by age and year also are available from the HCUP-KID, to allow estimates of incidence. The database used for the present study consisted of a stratified random sample across 6 years: 1997, 2000, 2003, 2006, 2009, and 2012. It contains approximately 3 million pediatric inpatient records per year from 4100 hospitals collected between 1997 and 2012. The database includes data from between 22 and 44 states, depending on the year. Each record in the database includes up to 25 diagnoses (15 before 2009) and 15 procedural codes based on the International Statistical Classification of Diseases and Related Health Problems, Ninth Revision (ICD-9). The HCUPKID assigns an individual-level population weight that allows for estimation of national case incidences and trends. The age in days at time of admission is reported for infants aged <1 year between 1997 and 2009.12 Variable Definition Case selection was performed by searching the database for children aged <1 year with the ICD-9 diagnostic code for biliary atresia (751.61) and for the procedure code for the Kasai hepatoportoenterostomy procedure (51.37). Criteria for inclusion in the study were the diagnosis code for biliary atresia and receipt of the Kasai hepatoportoenterostomy during hospitalization. In an effort to identify only incident cases of biliary atresia and to avoid duplicating subjects in the database, subjects identified as having undergone liver transplantation during hospitalization (50.5X, 998.1) were excluded. The population denominator data by year were obtained from the HCUP-KID.13 Demographic data included race, sex, and geographic region. The analysis of race/ethnicity was grouped into white, black, Hispanic, Asian/Pacific Islander, Native American, and other, based on race classification provided in the HCUP-KID. The hospital region was classified as Northeast, Midwest, South, or West. Statistical Analyses The overall and yearly incidences of biliary atresia were calculated by dividing the nationally weighted number of hospital admissions that met the study criteria by the total number of reported infants in the US population for the respective years. The estimated population of infants (ie, children aged <1 year) is reported by the HCUP-KID.14 The trends in biliary atresia were tested using the Cochrane-Armitage test of trend. Patient age at the time of Kasai hepatoportoenterostomy was calculated using age in days at the time of admission to the hospital as reported by the HCUP-KID. The age in days data represented only a subset of subjects, because available data were limited to the years 1997-2009. The age distribution at the time of Kasai hepatoportoenterostomy was found to be
Volume ■■ skewed and is reported as median (IQR). The Kruskal-Wallis test was used to test differences in age at the time of Kasai hepatoportoenterostomy across the years. The seasonality of biliary atresia was tested using the X11 procedure, an adaptation of the US Census Bureau’s X-11 Seasonal Adjustment program.15,16 A combination of 2 tests of seasonality—the stable seasonality test and moving seasonality test—was used. The stable seasonality test is a 1-way ANOVA on the detrended series with months as the factor. The moving seasonality test is a 2-way analysis that uses both months and years.15 The analyses were performed using the provided population weights as recommended by HCUP-KID documentation.12 Statistical analyses were performed using SAS version 9.3 (SAS Institute, Cary, North Carolina), and all statistical tests were performed at a significance level of a = 0.05. This study was reviewed and approved by the Uniformed Services University of the Health Sciences Institutional Review Board.
Results A total of 1057 nationally weighted cases of biliary atresia recorded in the US between 1997 and 2012 met the study cirteria. The overall incidence of biliary atresia in the US in 19972012 was 4.47 per 100 000 children age <1 year. The incidence of biliary atresia was higher in females than in males (5.36 per 100 000 vs 3.74 per 100 000; risk ratio [RR], 1.43; 95% CI, 1.27-1.62) (Table). Asian/Pacific Islanders had a higher incidence of biliary atresia compared with whites (7.55 per 100 000 vs 4.00 per 100 000; RR, 1.89; 95% CI, 1.442.47) or with blacks (5.18 per 100 000; RR, 1.30; 95% CI, 1.061.58). There was no significant difference in the incidence of biliary atresia across US regions (P = .29). The incidence of biliary atresia increased significantly over the study period, from 2.85 cases per 100 000 in 1997 to 5.55
Table. Demographics of biliary atresia in the US, 1997-2012
Variables Sex Female Male Race White Black Hispanic Asian/Pacific Islander Native American Other Unreported race Region Northeast Midwest South West
2
No. of biliary atresia cases
Incidence per 100 000 children
RR (95% CI)
610 446
5.36 3.74
1.43 (1.27-1.62) Reference
403 131 174 612 2 79 207
4.00 5.18 4.43 7.55 1.67 7.72 4.25
Reference 1.30 (1.06-1.58) 1.11 (0.93-1.32) 1.89 (1.44-2.47) 0.42 (0.10-1.67) 1.93 (1.52-2.46)
192 245 365 255
4.85 4.80 4.20 4.56
P value <.001 <.001 <.001 .26 <.001 .22 <.001 .29
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Figure 3. Number of biliary atresia cases per month in the US, demonstrating a lack of seasonality. Figure 1. Incidence of biliary atresia per 100 000 infants in the US, 1997-2012.
cases per 100 000 in 2012 (P < .001), an average annual percent increase of 7.9% (Figure 1). The overall median age at the time of Kasai hepatoportoenterostomy was 63 days (IQR, 47-76 days), and there was no significant change in age at the time of the Kasai procedure between 1997 and 2009 (P = .64) (Figure 2). When the cases of biliary atresia were separated by month, there was insufficient evidence of seasonality in the incidence of biliary atresia (P = .69) (Figure 3).
Discussion In published literature, the reported incidence of biliary atresia in the US ranges from 1 in 10 000 to 1 in 18 000 live births.17 A previous study in Atlanta, Georgia reported an incidence of biliary atresia of 1 in 14 000 between 1968 and 1993.18 A study done in New York reported an incidence of 1 in 11 800 live births in 1983-1998.17 Our study calculated a lower nationwide incidence of 1 in 22 371 infants between 1997 and 2012. This suggests that the overall incidence may have decreased since the 1970s. It also is possible that because our study relied on billing data, the incidence may be underrepresented owing to misclassification bias. This difference may represent a geo-
Figure 2. Median (IQR) age at the time of the Kasai hepatoportoenterostomy procedure in the US, 1997-2009.
graphical variation in biliary atresia, given that these studies were limited to 1 geographical area within the US. In the present study, however, there were no significant differences in the incidence of biliary atresia among the 4 main regions of the US as classified by the HCUP-KID. We found that the incidence of biliary atresia varied by sex and race. Female infants were at increased risk for biliary atresia compared with their male counterparts (RR, 1.43) (Table). Consistent with previous reports, we found that the incidence of biliary atresia varied by race. Compared with whites, Asian/ Pacific Islanders and blacks were at increased risk for biliary atresia, with 0.75 cases per 10 000 (RR, 1.89) and 0.52 cases per 10 000 (RR, 1.30), respectively (Table).10,18 The incidence of biliary atresia rose significantly during the study period, with the number of cases almost doubling from 1997 to 2012. This contrasts with the overall decreased incidence of biliary atresia reported in Taiwan from 2004 to 2009.10 Lin et al10 suggested a possible population-level natural cycle and fluctuation of biliary atresia. This hypothesis could explain the fluctuation that we noted in the US, with a higher incidence of biliary atresia from the 1970s to the early 1990s,17-19 followed by a lower incidence from the mid-1990s to the 2000s, and then a rise thereafter (Figure 1). Along with diagnostic bias, other factors contributing to this fluctuation could include racial and ethnic population changes, as well as environmental factors during pregnancy or the perinatal period. Viral infections have long been suspected to cause biliary atresia, specifically rotavirus, as studied in the murine model, which demonstrated that maternal rotavirus vaccination protected against rotavirus-induced murine biliary atresia.8 Lin et al theorized that the decreased incidence of biliary atresia could be due to the nationwide implementation of rotavirus vaccination in 2006.10 Even though rotavirus vaccination is usually administered after age 2 months, they postulated that herd immunity plays a role in protecting against biliary atresia during pregnancy or in the perinatal period, although the negative correlation of biliary atresia and vaccination rate was not significant (P = .07).10 Following implementation of the rotavirus vaccination program in 2006, rotavirus activity in the US declined dramatically, 20 although the incidence of biliary atresia
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THE JOURNAL OF PEDIATRICS • www.jpeds.com increased (Figure 1). Rotavirus infections typically occur during the winter months in temperate regions.21 Europe and North America had a prevalence of rotavirus of 37%-60% during the peak winter months and of 4%-11% in the summer months.22 A systematic review assessing the evidence for seasonal variation of biliary atresia worldwide found inconclusive data.23 In the present study, we found no significant seasonality of biliary atresia in the US (Figure 3). The lack of seasonality, together with a trend toward an increased prevalence of biliary atresia during the period of rotavirus vaccine implementation, suggests that rotavirus might not be associated with the development of biliary atresia. A caveat of this study is that implementation of a rotavirus vaccination program during the study period might have limited our ability to identify statistically significant seasonality possibly due to rotavirus. In our study, we found that >50% of all children with biliary atresia in the US underwent the Kasai procedure outside of the optimal window of 60 days of life, with a median age of 63 days (IQR, 47-76 days). In addition, patient age at the time of the Kasai procedure has remained stable from 1997 to 2009, suggesting that early identification of biliary atresia has not improved in the US (Figure 2). Because early diagnosis and the Kasai procedure are associated with greater survival of both the infant and his or her native liver, early detection of biliary atresia is important to allow performance of the Kasai procedure within the optimal window. The AAP’s technical report on newborn screening for biliary atresia underscores the importance of early identification of biliary atresia and discusses the feasibility of various biliary atresia screening methods for improving outcomes.11 One screening program involves the distribution of stool color cards with pictures of normal and abnormal stools, including claycolored, to parents to encourage them to seek prompt treatment for their infants with abnormal stools. Taiwan implemented a stool card screening program in 2002 and found that this program was associated with a significant increase in the number of early Kasai procedures, with 90% of cases diagnosed before 60 days of life.24 Mogul et al25 used a Markov model to determine that stool color card screening can be an economically feasible strategy to improve future biliary atresia outcomes in the US, with 30 life-years gained, 11 fewer liver transplants, 3 fewer deaths, and a $9 million decrease in total costs. Another, more objective screening method is to measure serum-conjugated or direct-reacting bilirubin concentrations as an early indicator of biliary atresia. Harpavat et al26 found that all infants with biliary atresia had elevated direct bilirubin/conjugated bilirubin as newborns, starting as early as 1 hour of life despite a normal total serum bilirubin level. These findings suggest that biliary atresia potentially can be identified before clinically significant liver injury occurs. These 2 screening methods, stool color card and direct bilirubin/conjugated bilirubin level, have the potential to significantly decrease the age at which Kasai hepatoportoenterostomy is performed. According to the AAP’s technical report, both stool color cards and conjugated bilirubin concentration have clinical validity as a potential screen-
Volume ■■ ing method for biliary atresia, with no significant clinical risk or harm to the infant. Further studies are warranted to determine the feasibility, effectiveness, and costs of these screening tools.11 Our definition of biliary atresia was based on ICD-9 coding. As in all studies using diagnostic codes, there is concern about possible misclassification and reporting bias, which could have led to a falsely low reported incidence of biliary atresia in this study. We attempted to minimize this bias by using diagnostic codes for both biliary atresia and Kasai hepatoportoenterostomy. Our study did not capture the rare patients with biliary atresia identified after age 1 year or those who were poor candidates for Kasai hepatoportoenterostomy and went directly to liver transplantation. This adds to the potential bias contributing to underestimation of the incidence of biliary atresia in the US. The identified trend toward an increasing prevalence of biliary atresia possibly can be explained by better identification of infants with biliary atresia. A major strength of our study is that the HCUP-KID provides an excellent national representative sample of pediatric hospitalizations rather than just a sample from a specific region, allowing us to examine the epidemiology of biliary atresia across the US. The HCUP-KID, the largest inpatient pediatric database in the US, provides robust national estimates of hospitalized diseases; nonetheless, sampling bias might have impacted our calculated estimates of biliary atresia. According to the HCUP-KID documentation in 2012, the database captured a representative sample of 95.6% of pediatric hospitalizations in the US.12 The HCUP-KID does not include all inpatient records, but does include records from all types of hospitals. Although the HCUP-KID–provided weights account for the poststratification sampling design of the database, Kasai hepatoportoenterostomies likely would be performed more often at children’s hospitals, thus potentially introducing sampling bias. ■ Submitted for publication Oct 21, 2016; last revision received Apr 10, 2017; accepted May 2, 2017 Reprint requests: Perri Hopkins, MD, San Antonio Military Medical Center, Pediatric Residency Program, 3551 Roger Brooke Dr, JBSA Fort Sam Houston, TX 78234. E-mail: [email protected].
References 1. Suchy FJ, Burdelski M, Tomar BS, Sokol RJ. Cholestatic liver disease: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr 2002;35(Suppl 2):S89-97. 2. Nio M, Ohi R, Miyano T, Saeki M, Shiraki K, Tanaka K, et al. Five- and 10-year survival rates after surgery for biliary atresia: a report from the Japanese Biliary Atresia Registry. J Pediatr Surg 2003;38:9971000. 3. Ohi R. Surgery for biliary atresia. Liver 2001;21:175-82. 4. Shneider BL, Brown MB, Haber B, Whitington PF, Schwarz K, Squires R, et al. A multicenter study of the outcome of biliary atresia in the United States, 1997 to 2000. J Pediatr 2006;148:467-74. 5. Suchy FJ. Neonatal cholestasis. Pediatr Rev 2004;25:388-96. 6. Serinet MO, Wildhaber BE, Broué P, Lachaux A, Sarles J, Jacquemin E, et al. Impact of age at Kasai operation on its results in late childhood and adolescence: a rational basis for biliary atresia screening. Pediatrics 2009;123:1280-6.
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17. Caton AR, Druschel CM, McNutt LA. The epidemiology of extrahepatic biliary atresia in New York State, 1983-98. Paediatr Perinat Epidemiol 2004;18:97-105. 18. Yoon PW, Bresee JS, Olney RS, James LM, Khoury MJ. Epidemiology of biliary atresia: a population-based study. Pediatrics 1997;99:376-82. 19. Sokol RJ, Mack C, Narkewicz MR, Karrer FM. Pathogenesis and outcome of biliary atresia: current concepts. J Pediatr Gastroenterol Nutr 2003;37:421. 20. Tate JE, Mutuc JD, Panozzo CA, Payne DC, Cortese MM, Cortes JE, et al. Sustained decline in rotavirus detections in the United States following the introduction of rotavirus vaccine in 2006. Pediatr Infect Dis J 2011;30(1 Suppl):S30-4. 21. Cook SM, Glass RI, LeBaron CW, Ho MS. Global seasonality of rotavirus infections. Bull World Health Organ 1990;68:171-7. 22. Patel MM, Pitzer VE, Alonso WJ, Vera D, Lopman B, Tate J, et al. Global seasonality of rotavirus disease. Pediatr Infect Dis J 2013;32:e13447. 23. Jimenez-Rivera C, Jolin-Dahel KS, Fortinsky KJ, Gozdyra P, Benchimol EI. International incidence and outcomes of biliary atresia. J Pediatr Gastroenterol Nutr 2013;56:344-54. 24. Lien TH, Chang MH, Wu JF, Chen HL, Lee HC, Chen AC, et al. Effects of the infant stool color card screening program on 5-year outcome of biliary atresia in Taiwan. Hepatology 2011;53:202-8. 25. Mogul D, Zhou M, Intihar P, Schwarz K, Frick K. Cost-effective analysis of screening for biliary atresia with the stool color card. J Pediatr Gastroenterol Nutr 2015;60:91-8. 26. Harpavat S, Finegold MJ, Karpen SJ. Patients with biliary atresia have elevated direct/conjugated bilirubin levels shortly after birth. Pediatrics 2011;128:e1428-33.
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