Abstract
Objectives
The etiology of biliary atresia (BA) is unclear and potentially involves viral triggers. We aimed to compare the incidence of BA in the United States before and during the coronavirus disease 2019 (COVID‐19) pandemic, focusing on potential associations with viral circulation disruptions caused by nonpharmaceutical interventions (NPIs).
Methods
We queried the Pediatric Health Information System® (PHIS) for all patients discharged with BA between January 1, 2010, and January 31, 2024. Using CDC WONDER, we calculated monthly and overall incidence rates of BA per 1,000,000 live births. We fit a Poisson regression model to assess the association between the widespread implementation of stay‐at‐home orders (using April 1, 2020, as the cutoff date) and the incidence of BA, accounting for national natality fluctuations.
Results
We identified 3456 newborns with BA from 42 hospitals; 2997 (86.7%) were born before and 459 (13.3%) were born during the pandemic. The mean monthly number of newborns with BA was 24.0 (95% confidence interval, 23.0–25.0) for an overall incidence rate of 74.4 (71.5–77.4) per 1,000,000 live births. We did not identify a statistically significant year‐to‐year contrast in the incidence of BA before (incidence rate ratio [IRR] = 0.995 [0.983–1.008]; p = 0.49) or after the cutoff date (IRR = 0.999 [0.895–1.116]; p = 0.99). In addition, we did not identify sufficient evidence that trends differed between the two periods (IRR = 1.004 [0.893–1.128]; p = 0.95). [Correction added on 26 February 2025, after the first online publication: The point estimate for the IRR has been updated to 1.004.]
Conclusions
The NPIs implemented during the COVID‐19 pandemic were not significantly associated with changes in the incidence or temporal pattern of BA.
Keywords: communicable disease control, epidemiology, health information systems, newborns
What is Known
The pathogenesis of biliary atresia is likely multifactorial.
One hypothesis involves viral triggers causing inflammation and fibrosis in the biliary tree, with varying findings described in both human and animal studies.
The social mitigation efforts implemented during the COVID‐19 pandemic disrupted viral circulation.
What is New
This unique natural experiment allows us to investigate whether these efforts were associated with a decrease in the incidence of biliary atresia in the United States.
We did not identify sufficient evidence of a significant change in the incidence of biliary atresia before and during the pandemic.
1. INTRODUCTION
Biliary atresia (BA) is a perplexing disease of young infancy, causing progressive inflammation, fibrosis, and obstruction of the intrahepatic and extrahepatic bile ducts. The consequences of untreated BA are devastating, leading to life‐threatening end‐stage liver fibrosis and failure in infants. Management usually begins with the timely performance of a hepatoportoenterostomy (Kasai procedure) to reestablish biliary flow and drainage. However, even with this procedure, most patients still require liver transplantation within 2 years. 1 , 2 A consensus on the pathogenesis of BA has yet to be achieved. Various hypotheses, including genetically driven development defects in the biliary tract, 3 defective embryogenesis, 1 autoimmunity, 4 and viral infection‐associated inflammation, 5 , 6 including multifactorial etiology, have been proposed and studied.
Rotavirus, reovirus, cytomegalovirus (CMV), and Epstein–Barr virus are among the most studied pathogens in relation to BA. 5 , 7 , 8 , 9 , 10 , 11 , 12 Results from studies in animal models and humans have been inconsistent, with some reporting higher levels of pathogen‐specific antibodies in the biliary tracts of subjects with BA and others reporting insignificant differences in antibody titer levels. 13 , 14 Additionally, the timing of viral exposure and its role in the development of BA remain unclear, though most, if not all, forms of BA may start before birth, based on laboratory, imaging, and clinical data. 15
The coronavirus disease 2019 (COVID‐19) pandemic caused worldwide implementation of nonpharmaceutical interventions (NPIs) to control disease spread. 16 , 17 , 18 As a result, the circulation and seasonality of many common respiratory viruses were disrupted, with many skipping an entire viral season and rising again after community mitigation measures were less strictly implemented. 19 , 20 , 21 , 22 Therefore, we aimed to compare the incidence of BA before and during the COVID‐19 pandemic in the United States, hypothesizing that if the viruses disrupted by NPIs play a significant role in BA pathogenesis, we would observe an altered incidence of BA during the pandemic.
2. METHODS
2.1. Study design
The Pediatric Health Information System® (PHIS) is an administrative database that aggregates encounter‐level clinical and financial data from 48 children's hospitals in the United States (as of January 2024). The PHIS database includes children's hospitals that are typically the dominant pediatric provider in their respective markets and so is likely representative of most tertiary or quaternary pediatric care in the nation, such as that required for BA, although no official estimates to that effect are available. We used the PHIS Cohort Builder, an online tool developed by the Children's Hospital Association, to query the PHIS database for all patients discharged between January 1, 2010, and January 31, 2024, with a primary or secondary diagnosis code for BA. Because ICD‐10‐CM superseded ICD‐9‐CM as the mandated system for medical coding in the United States on October 1, 2015, we included the ICD‐9‐CM code 751.61 and the ICD‐10‐CM code Q44.2 to identify BA cases across the study years. We excluded hospitals with discontinuous data contributions throughout the study years to ensure a steady‐state population. To construct the most comprehensive cohort possible, we pulled all episodes of care associated with either diagnosis code and collapsed the fully inclusive encounter‐level cohort to an individual‐level cohort using a one‐way hashed medical record number that serves as an encrypted unique identifier for each individual. To describe the demographic characteristics of the cohort, we retrieved the following variables systematically collected by PHIS: sex assigned at birth, race, Hispanic origin, census region, and census division. Race and Hispanic origin, which are social constructs, were assigned according to hospital‐specific policies: We described race and Hispanic origin in aggregate because previous reports on BA have identified evidence of racial and ethnic disparities and inequities. 23
In the main analysis, we restricted the cohort to those born between January 1, 2010, and December 31, 2021, a cutoff date chosen to include the pandemic period during which viral circulation was most significantly impacted by NPIs, so as not to dilute the observed effect of the “natural experiment” created by the pandemic‐related disruption in viral circulation. 24 To account for normal monthly fluctuations in births, we obtained national monthly natality data from the Centers for Disease Control and Prevention (CDC) National Vital Statistics System using CDC WONDER (Wide‐ranging ONline Data for Epidemiologic Research). We used April 1, 2020, as the cutoff date of birth to compare the incidence of BA because 42 United States and territories issued mandatory stay‐at‐home orders between March 1, 2020, and May 31, 2020. 25
2.2. Ethics statement
The study protocol was reviewed and approved by the Vanderbilt University Institutional Review Board (IRB; number 240180).
2.3. Statistical methods
Unless otherwise stated, we described categorical variables using absolute and relative frequencies and continuous variables using the mean (95% confidence intervals [CIs] were also determined for continuous variables). We compared categorical variables using Pearson's χ 2 test. To examine trends over time, we calculated monthly and overall incidence rates of BA per 1,000,000 live births. The numerator for the incidence rate was the number of individuals born in a given time interval with BA. The denominator was the number of live births nationally for that given time interval. We used Poisson regression to formally characterize the incidence of BA over time and evaluate the effect of widespread implementation of stay‐at‐home orders on its incidence. Counts were aggregated at the monthly level with the outcome being the number of newborns with BA and the offset being the number of live births. To allow for a change in the trend of BA incidence after the implementation of stay‐at‐home orders, we modeled the log rate as a continuous piecewise linear function with a single knot placed on April 1, 2020. In our main analysis, we used the date of birth as the reference point, assuming that the trigger causing BA occurs at birth. However, considering the possibility that the insult may occur earlier in gestation, with the earliest hypothesized occurrence at Week 12 of gestation, we conducted a sensitivity analysis to assess the robustness of our findings to the assumption regarding the timing of the potential trigger for BA. 26 In this analysis, we used the date corresponding to gestational Week 12 as the reference point. To calculate this date, we used the gestational age at birth, which was available for a subset of patients. For individuals whose gestational age at birth was missing, we imputed a value of 39 weeks, the median for singleton live births in the United States. 27 To assess for autocorrelation, we plotted the deviance residuals over time and visually inspected the plot for any patterns or systematic deviations from randomness. We used R (version 4.3.2) to perform all analyses and interpreted the statistical significance of p‐values based on a nominal threshold of α = 0.05 (two‐sided).
3. RESULTS
3.1. Study sample
Between January 1, 2010, and January 31, 2024, 95,346,852 episodes of care were captured in PHIS, 39,110 of which were associated with a primary or secondary diagnosis code for BA. We initially identified 3575 individuals born between January 1, 2010, and December 31, 2021, with BA. We dropped 119 cases (3.3%) from hospitals with discontinuous data contribution throughout the study period for a final analytic sample of 3456 individuals from 42 hospitals. Of the total, 2,997 (86.7%) were born before the COVID‐19 pandemic and 459 (13.3%) were born during the pandemic (using the April 1, 2020, cutoff).
The mean monthly number of newborns with BA during the study period was 24.0 (95% CI, 23.0–25.0), and the overall incidence rate of BA per 1,000,000 live births was 74.4 (71.5–77.4). Of the 3456 individuals in our analysis, 1892 (54.7%) were female and 1564 (45.3%) were male. The Pacific was represented more so than any other census region, with 656 individuals from the Pacific comprising 19.0% of the cohort. The demographic characteristics of the study sample, stratified by timing of birth in relation to the onset of the COVID‐19 pandemic, are compared in Table 1.
Table 1.
Demographic characteristics of N = 3456 individuals born between January 1, 2010, and December 31, 2021, with biliary atresia, stratified by the timing of birth relative to the onset of the COVID‐19 pandemic (using April 1, 2020, as the cutoff date). p‐values were calculated using Pearson's χ 2 test.
| Characteristic | Overall, N = 3456 | Before the pandemic, n = 2997 | During the pandemic, n = 459 | p‐Value |
|---|---|---|---|---|
| Sex assigned at birth—n (%) | 0.94 | |||
| Female | 1892 (54.7) | 1640 (54.7) | 252 (54.9) | |
| Male | 1564 (45.3) | 1357 (45.3) | 207 (45.1) | |
| Race and Hispanic origin—n (%) | 0.085 | |||
| Hispanic | 740/3165 (23.4) | 624/2745 (22.7) | 116/420 (27.6) | |
| Non‐Hispanic American Indian or Alaska Native | 20/3165 (0.6) | 17/2745 (0.6) | 3/420 (0.7) | |
| Non‐Hispanic Asian | 203/3165 (6.4) | 182/2745 (6.6) | 21/420 (5.0) | |
| Non‐Hispanic Black | 506/3165 (16.0) | 429/2745 (15.6) | 77/420 (18.3) | |
| Non‐Hispanic Native Hawaiian or Other Pacific Islander | 23/3165 (0.7) | 21/2745 (0.8) | 2/420 (0.5) | |
| Non‐Hispanic White | 1673/3165 (52.9) | 1472/2745 (53.6) | 201/420 (47.9) | |
| Census region—n (%) | 0.56 | |||
| South | 1063 (30.8) | 936 (31.2) | 127 (27.7) | |
| West South Central | 559 (16.2) | 494 (16.5) | 65 (14.2) | |
| South Atlantic | 416 (12.0) | 365 (12.2) | 51 (11.1) | |
| East South Central | 88 (2.5) | 77 (2.6) | 11 (2.4) | |
| West | 909 (26.3) | 784 (26.2) | 125 (27.2) | |
| Pacific | 656 (19.0) | 569 (19.0) | 87 (19.0) | |
| Mountain | 253 (7.3) | 215 (7.2) | 38 (8.3) | |
| Midwest | 840 (24.3) | 719 (24.0) | 121 (26.4) | |
| East North Central | 558 (16.1) | 484 (16.1) | 74 (16.1) | |
| West North Central | 282 (8.2) | 235 (7.8) | 47 (10.2) | |
| Northeast | 644 (18.6) | 558 (18.6) | 86 (18.7) | |
| Middle Atlantic | 470 (13.6) | 412 (13.7) | 58 (12.6) | |
| New England | 174 (5.0) | 146 (4.9) | 28 (6.1) |
Abbreviation: COVID‐19, coronavirus disease 2019.
3.2. Trends in the incidence of BA
To evaluate trends in the incidence of BA over time, we calculated the monthly incidence rate. Across the 12‐year study period, the monthly incidence varied considerably, reaching a nadir of 25.3 per 1,000,000 live births in May 2019 and peaking at 121.5 in July 2011 (Figure 1). The overall incidence rate before the widespread implementation of stay‐at‐home orders (using April 1, 2020, as the cutoff date of birth) was 74.8 (71.4–78.0), while the overall incidence rate for those born between April 1, 2020, and December 31, 2021, was 72.1 (63.4–80.8). We found insufficient evidence that trends in the incidence of BA over time statistically significantly differed after the implementation of stay‐at‐home orders compared with prior trends (incidence rate ratio [IRR] = 1.004 [0.893–1.128]; p = 0.95). In addition, we did not identify a statistically significant year‐to‐year contrast in the incidence rate of BA before the pandemic (IRR = 0.995 [0.983–1.008]; p = 0.49). Similarly, we did not find a statistically significant year‐to‐year contrast in the incidence rate of BA after the implementation of stay‐at‐home orders (IRR = 0.999 [0.895–1.116]; p = 0.99). Based on a visual assessment of deviance residuals, we did not observe any strong evidence of autocorrelation.
Figure 1.

Monthly incidence rate of biliary atresia in the United States (January 01, 2010–December 31, 2021). The x‐axis represents the date of birth. The model‐based predicted incidence rate (blue line) and 95% pointwise confidence band (light gray) are shown. The dashed line separates the periods before and after widespread stay‐at‐home orders.
3.3. Sensitivity analysis
Gestational age at birth was available for 1242 (36.1%) of the 3439 individuals included in a sensitivity analysis using the date corresponding to gestational week 12 as the reference point. The median gestational age at birth was 38 weeks (interquartile range, 36–39). The results of the sensitivity analysis were consistent with the main findings, demonstrating insufficient evidence of a change in the incidence of BA during the pandemic (Figure 2).
Figure 2.

Monthly incidence rate of biliary atresia in the United States (January 01, 2010–December 31, 2021). The x‐axis represents the date at gestational Week 12. The model‐based predicted incidence rate (blue line) and 95% pointwise confidence band (light gray) are shown. The dashed line separates the periods before and after widespread stay‐at‐home orders.
4. DISCUSSION
In this retrospective cohort study, we used PHIS to identify 3278 individuals born between 2010 and 2021 with BA. We estimated that the overall incidence rate of BA during the 12‐year study period was 74.4 per 1,000,000 live births, consistent with previously reported estimates. 28 , 29 Despite the considerable variability in monthly incidence rates, our analysis suggests that the substantial public health restrictions implemented during the COVID‐19 pandemic were not significantly associated with the overall incidence rate or temporal patterns of BA.
The NPIs and social mitigation efforts employed during the pandemic disrupted the circulation of various respiratory viruses. Rankin et al. reported a lower proportion of encapsulated respiratory viruses circulating during the pandemic compared to the pre‐pandemic period. 30 Similar findings were observed in several other studies conducted globally. 16 , 17 , 18 , 19 , 20 , 21 , 31 These results provide a unique opportunity to explore the hypothesis that viral triggers, in particular pathogens transmitted via the fecal–oral route or oral secretions, could play a role in the pathogenesis of BA.
Several viruses, including rotavirus, reovirus, CMV, and Epstein–Barr virus, have been investigated for their potential role in the pathogenesis of BA due to their hepatotropic properties, which could theoretically contribute to the development of BA via inflammation and immune‐mediated hepatic injury in susceptible hosts. Among these, CMV has been a focus of research, but results have been largely inconclusive due to limitations such as small sample sizes, inconsistency in study designs, and the inability to obtain biopsy results from healthy controls. 5 Notably, studies from Portugal and Minnesota reported a decrease in the prevalence of congenital CMV during the pandemic compared to the pre‐pandemic period. 32 , 33 While we cannot generalize these results to represent CMV circulation across the United States, we did not observe any notable changes in the incidence rate of BA during the pandemic. Given the likely multifactorial etiology of BA, the observed null association could also theoretically reflect the countervailing effects of NPIs on multiple causal pathways, potentially masking the impact of changes in viral circulation.
Recent studies have examined potential changes in the incidence of BA in Europe during the COVID‐19 pandemic, yielding varying results. Nomden et al. 34 reported an inverse correlation between lockdown stringency (measured using the “stringency index”) and the percent change in the mean monthly number of newborns with BA. While intriguing, this was a finding from a sensitivity analysis, whereas the main analysis and other analyses produced insufficient evidence of a change. Given the rarity of BA, percent changes in monthly means should be carefully considered because the estimate is liable to extreme values due to near‐zero monthly means. Arshad et al. 35 reported a lower‐than‐expected count of BA cases during the first lockdown in England and Wales but not the second, with insufficient evidence of any changes in the annual numbers (despite persistent disruption of the circulation of many viruses beyond lockdown periods). These studies contribute valuable perspectives, though their findings highlight methodological challenges and limitations commonly encountered in studying rare or poorly understood diseases, including the lack of adjustment for the population at risk, inconsistency in findings, analytic multiplicity, and the potential introduction of high sampling variability due to short observation periods in tandem with small sample sizes. Therefore, further research is necessary to help clarify the relationship between viral triggers and the incidence of BA in the context of the “natural experiment” that the COVID‐19 pandemic offered.
Our study has several strengths, including 12 years of continuous data, a large cohort size, and representation of a substantial proportion of BA cases across the United States. However, it is important to acknowledge certain limitations. First, while we captured a large proportion of BA cases, we may still be underestimating the true incidence of BA. Nevertheless, our steady‐state population allows for a high degree of confidence in our findings, assuming no significant changes in population dynamics and movement over the study period. Second, we were unable to independently evaluate the circulation of viruses commonly associated with BA as comprehensive data on their circulation before and during the pandemic is lacking. Third, the timing of BA onset remains unclear, which could affect the validity of the cutoff dates we selected for our analysis. Finally, in our sensitivity analysis using gestational Week 12 as a reference point, the gestational age at birth was available for only 36.1% of infants, necessitating imputation for the remainder. The high proportion of imputed data may affect the robustness of results from our sensitivity analysis, which must be interpreted with caution.
5. CONCLUSIONS
Our findings suggest that the COVID‐19 pandemic was not significantly associated with changes in the incidence of BA across the United States. The pathogenesis of BA is likely multifactorial, involving a complex interplay of genetic, immunologic, and environmental factors. Our results contribute to the ongoing discussion about BA etiology but further research is needed to better understand the specific factors contributing to BA pathogenesis and to develop targeted prevention and treatment strategies.
CONFLICT OF INTEREST STATEMENT
A.J.S. reports grant support from the National Institutes of Health. N.B.H. received grant support from Sanofi and Quidel, receives current grant support from Merck, and served on an advisory board for CSL Seqirus. The remaining authors have no conflicts of interest relevant to this article to disclose.
ACKNOWLEDGMENTS
Data for this study were obtained from the Pediatric Health Information System® (PHIS), an administrative database that contains inpatient, emergency department, ambulatory surgery, and observation encounter‐level data from not‐for‐profit, tertiary‐care pediatric hospitals in the United States. These hospitals are affiliated with the Children's Hospital Association (Lenexa, KS). Data quality and reliability are assured through a joint effort between the Children's Hospital Association and participating hospitals. For external benchmarking, participating hospitals provide discharge/encounter data, including demographics, diagnoses, and procedures. Nearly all these hospitals also submit resource utilization data (e.g., pharmaceuticals, imaging, and laboratory) into PHIS. Data are deidentified at the time of data submission, and data are subjected to several reliability and validity checks before being included in the database. For this study, data from 42 hospitals was included.
Qwaider YZ, Amarin JZ, Spieker AJ, et al. Incidence of biliary atresia in the United States before and during the COVID‐19 pandemic. J Pediatr Gastroenterol Nutr. 2025;80:943‐949. 10.1002/jpn3.70009
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