Blackwell Science, LtdOxford, UKPPEPaediatric and Perinatal Epidemiology1365-3016Blackwell Publishing Ltd, 200318••97105Original ArticleThe epidemiology of extrahepatic biliary atresia in NYSA. R. Caton
et al.
97
Original articles
The epidemiology of extrahepatic biliary atresia in New York State,
1983–98
Alissa R. Catona, Charlotte M. Druschela,b and Louise A. McNutta
a
Department of Epidemiology, School of Public Health, University at Albany, NY, and bCongenital Malformations Registry, New York State
Department of Health, NY, USA
Summary
Correspondence:
Alissa Caton, Department of
Epidemiology, School of
Public Health, University at
Albany, One University Place,
Rensselaer, NY 12144, USA
E-mail:
[email protected]
The aetiology of biliary atresia, the leading cause of neonatal extrahepatic jaundice
and the main indication for liver transplantation in children, is unknown. Recent
research has focused on an infectious aetiology and the development of viral models
in animals. The few published epidemiological studies report conflicting results for
seasonal, geographical, and racial variations in incidence. In this study, New York State
(NYS) Congenital Malformations Registry data from 1983 to 1998 were compared with
resident live birth certificate data. County of residence, birth date, gestational age,
birthweight, gender, maternal race and maternal age were extracted from the birth
certificate data. Isolated and sequence cases were combined for analysis. Observed
and expected numbers of cases were calculated by NYS region.
Overall, 369 biliary atresia cases were reported in the 16-year study period, a rate
of 0.85 [95% CI 0.76, 0.93] per 10 000 live births. Of these, 249 isolated/sequence cases
were ascertained, a rate of 0.57 [95% CI 0.50, 0.64] per 10 000 live births. The rate ratio
of biliary atresia in New York City (NYC) compared with other NYS was 2.19 [95% CI
1.69, 2.84]. Seasonal patterns varied by region with spring births at highest risk in NYC
and September to November births at highest risk in other NYS. The rate ratio in black
vs. white mothers was 1.94 [95% CI 1.48, 2.54]. Birthweight and gestational age were
associated with biliary atresia with preterm low-birthweight infants at highest risk [RR
3.24, 95% CI 2.20, 4.76]. The association of isolated/sequence biliary atresia with
season, preterm birth, and low birthweight in our study supports an infectious disease
hypothesis.
Introduction
Biliary atresia is the leading cause of extrahepatic
obstructive jaundice in neonates and the leading indication for liver transplantation in children.1 Two
hypothesised forms of the disease have been
described.1–3 The embryonic form is characterised by
early onset of neonatal cholestasis, lack of a jaundicefree interval after physiological jaundice, lack of bile
duct remnants, and associated congenital anomalies.
The perinatal or acquired form, characterised by a later
onset, bile duct remnants, and lack of associated anomalies, is thought to be caused by an infectious agent or
environmental toxin.4 Recent laboratory research has
focused on an infectious aetiology, and viral models
have been developed in animals.5–31 The viral suspects
include cytomegalovirus,5–11 reovirus type 3,12–23 and
rotavirus A-C.24–31
Only a few epidemiological studies of biliary
atresia have been published.32–40 In these studies,
conflicting results for seasonal and geographical
variations in incidence have been reported. In
addition, the association of biliary atresia with
race and low birthweight is not clear. To explore
further these seasonal and geographical differences in the incidence of the perinatal form of
biliary atresia, 16 years of live birth data from a
large population-based registry were analysed in
this study.
© Blackwell Publishing Ltd. Paediatric and Perinatal Epidemiology 2004, 18, 97–105
98
A. R. Caton et al.
were combined to represent the perinatal form for
the analyses.
Methods
Data sources and study population
The New York State Congenital Malformations Registry is one of the largest statewide, populationbased birth defects registries in the United States.
New York hospitals and physicians are required by
law to report to the Registry malformations not
resulting from birth trauma in children under 2 years
of age who are born in or reside in New York. Individual cases are reported on forms provided by the
New York State Department of Health. Case information, including the narrative description of the
malformation, is reviewed and coded. The case is
matched to existing Registry reports for possible
duplicates.41
Records of biliary atresia cases were extracted from
the Registry for the years 1983 to 1998. Cases were
matched to New York State live birth certificate records
by year of birth and birth certificate number. Resident
live birth certificate data for the same years were used
to represent the population at risk.
Case classification
Biliary atresia cases were selected from the Registry
using the International Classification of Diseases,
Ninth Revision (ICD9) code 751.61 for the 1983 to
1991 data, and the modified British Paediatric Association (BPA) code 751.65 was used for the 1992 to
1998 data. Biliary atresia was represented by one
specific code in each scheme. The embryonic form of
the disease is associated with multiple anomalies,
whereas the perinatal form is not. To distinguish
between the two hypothesised forms of the disease,
records of the biliary atresia cases were reviewed to
separate cases with multiple malformations or syndromes from the perinatal analysis group. Cases
without additional reported malformations or with a
minor unrelated anomaly, such as umbilical hernia,
were classified as isolated events. Cases with related
hepatobiliary anomalies considered as sequelae of
biliary atresia (e.g. disorders of bilirubin excretion)
were classified as sequence events. Trisomies were
categorised as syndromes. The remaining records of
cases with additional major malformations were classified as multiple anomalies. Since it is hypothesised
that the perinatal form of biliary atresia has an environmental aetiology, the isolated and sequence cases
Study variables
County of residence, date of birth, birthweight, gestational age in weeks, gender, maternal race, and maternal age were collected from the computerised birth
certificate data files. County of residence was grouped
into New York City and other New York State categories. Year and month of birth were created from date
of birth. Month of conception was estimated using gestational age in weeks and date of birth. Month of birth
was collapsed into four seasons: winter (December–
February), spring (March–May), summer (June–
August), and autumn (September–November).
Birthweight was grouped as low birthweight (<2500 g)
and normal birthweight (≥2500 g). Gestational age was
categorised as preterm (<37 weeks) and term (≥37
weeks). To be comparable with Yoon et al.38 birthweight and gestational-age were used to create weight
for gestational age categories as defined by the Centers
for Disease Control and Prevention: preterm low birthweight, preterm normal birthweight, term low birthweight, and term normal birthweight.42 Maternal race
was categorised as white, black, and other. Maternal
age was grouped as <25, 25–34, ≥ 35 years.
Statistical analyses
Biliary atresia incidence rates with 95% confidence
intervals [95% CI] were calculated for isolated/
sequence cases. Observed and expected frequencies for
county of residence, year of birth, and month of birth
were calculated, assuming a constant incidence of disease. Chi-square tests were used to assess statistically
significant variations. Three-year and 3-month moving
average rates were calculated by region. The Walter
and Elwood test for seasonality with a variable population at risk was used for months of birth and conception.43 Crude and multivariable Poisson regression
analyses were performed and 95% CIs were calculated
for region, season of birth, weight for gestational age,
maternal race, maternal age, and gender categories. As
~46% of live births were to residents of New York City,
an area that accounts for < 1% of the total area of New
York State, separate crude and multivariable Poisson
regression analyses were performed for New York City
and other New York State.
© Blackwell Publishing Ltd. Paediatric and Perinatal Epidemiology 2004, 18, 97–105
The epidemiology of extrahepatic biliary atresia in NYS
99
Table 1. New York State live birth infant characteristics by region, 1983–98
Total New York State
Variable
Region
New York City
Other New York State
Season of birtha
Winter
Spring
Summer
Autumn
WGAb
Preterm LBW
Preterm NBW
Term LBW
Term NBW
Maternal race
White
Black
Other
Gender
Female
Male
Maternal age (years)
<25
25–34
≥35
a
New York City
Other New York State
n
%
n
%
n
%
1 988 711
2 377 229
45.6
54.5
1 988 711
100.0
2 377 229
100.0
1 039 489
1 100 469
1 140 979
1 085 003
23.8
25.2
26.1
24.9
484 720
488 939
514 897
500 155
24.4
24.6
25.9
25.2
554 769
611 530
626 082
584 848
23.3
25.7
26.3
24.6
192 123
185 243
131 933
3 729 369
4.5
4.4
3.1
88.0
101 407
98 326
74 807
1 652 374
5.3
5.1
3.9
85.8
90 716
86 917
57 126
2 076 995
3.9
3.8
2.5
89.8
3 204 596
922 686
238 658
73.4
21.1
5.5
1 133 414
684 558
170 739
57.0
34.4
8.6
2 071 182
238 128
67 919
87.1
10.0
2.9
2 127 020
2 234 591
48.8
51.2
969 625
1 017 127
48.8
51.2
1 157 395
1 217 464
48.7
51.3
1 394 081
2 431 241
537 504
32.0
55.7
12.3
692 061
1 038 151
256 786
34.8
52.3
12.9
702 020
1 393 090
280 718
29.6
58.6
11.8
Winter, December–February; Spring, March–May; Summer, June–August; Autumn, September–November.
WGA, weight for gestational age; Preterm, < 37 weeks; Term, ≥37 weeks; LBW, < 2500 g; NBW, ≥2500 g.
b
Results
Study population characteristics and case
ascertainment
For the 16-year study period, 4 365 940 resident live
births were recorded in New York State. Table 1
shows the distribution of risk factors in the study
population by region. A total of 369 biliary atresia
cases was extracted from the Congenital Malformations Registry, a rate of 0.85 [95% CI 0.76, 0.93] per
10 000 live births. Of these, 112 cases were associated with multiple anomalies and eight were associated with syndromes. Two hundred and fortynine (67%) of the cases were classified as isolated
or sequence events, a rate of 0.57 [95% CI 0.50,
0.64] per 10 000 live births. The rate of isolated/
sequence biliary atresia in New York State did not
vary significantly by year during the 16-year study
period.
Geographical and seasonal variation
Forty-six per cent of the New York State live births
during the study period were born to mothers residing
in New York City (Table 1), and 161 (65%) of the isolated/sequence biliary atresia cases were from this
region. Table 2 shows that the rate ratio for New York
City compared with the rest of New York State was
2.19 [95% CI 1.69, 2.84]. After controlling for weight for
gestational age, season of birth, maternal race, and
gender with multivariable Poisson regression analysis,
the rate ratio remained significant at 1.83 [95% CI 1.38,
2.42].
The yearly rate of biliary atresia in New York City
births did not vary significantly over the 16-year
period. However, the biliary atresia rate in the other
New York State region varied significantly over the
study period with a P-value of 0.004. Figure 1 shows
the smoothed rates over time. At the beginning of the
study period, the difference in rates between the
© Blackwell Publishing Ltd. Paediatric and Perinatal Epidemiology 2004, 18, 97–105
1.00 Reference
1.94 [1.48, 2.54]
1.83 [1.15, 2.91]
1.04 [0.81, 1.34]
1.00 Reference
1.00 Reference
0.93 [0.70, 1.22]
1.18 [0.80, 1.75]
147
82
20
124
125
81
131
37
[2.20, 4.76]
[1.07, 2.98]
[1.62, 4.39]
Reference
3.24
1.79
2.67
1.00
30
16
17
180
[0.81, 1.73]
[0.87, 1.83]
Reference
[1.18, 2.37]
1.18
1.26
1.00
1.67
2.19 [1.69, 2.84]
1.00 Reference
RR [95% CI]
55
62
51
81
161
88
n
1.00 Reference
1.04 [0.79, 1.39]
1.28 [0.85, 1.88]
1.03 [0.80, 1.32]
1.00 Reference
1.00 Reference
1.40 [1.04, 1.88]
1.50 [0.90, 2.35]
2.92 [1.94, 4.24]
1.65 [0.95, 2.67]
2.36 [1.38, 3.78]
1.00 Reference
1.21 [0.82, 1.79]
1.30 [0.90, 1.91]
1.00 Reference
1.66 [1.17, 2.39]
1.83 [1.38, 2.42]
1.00 Reference
aRR [95% CI]
54
80
27
79
82
78
67
16
21
7
10
118
37
45
36
43
n
1.00 Reference
0.99 [0.70, 1.39]
1.35 [0.85, 2.14]
1.01 [0.74, 1.38]
1.00 Reference
1.00 Reference
1.42 [1.03, 1.97]
1.36 [0.80, 2.33]
2.90 [1.82, 4.61]
1.00 [0.47, 2.14]
1.87 [0.98, 3.57]
1.00 Reference
1.09 [0.69, 1.73]
1.32 [0.85, 2.04]
1.00 Reference
1.23 [0.79, 1.91]
RR [95% CI]
New York City
b
Winter, December–February; Spring, March–May; Summer, June–August; Autumn, September–November.
WGA, weight for gestational age; Preterm, <37 weeks; Term, ≥37 weeks; LBW, <2500 g; NBW, ≥2500 g.
RR, rate ratio; aRR, adjusted rate ratio.
a
Region
New York City
Other New York State
Season of birtha
Winter
Spring
Summer
Autumn
WGAb
Preterm LBW
Preterm NBW
Term LBW
Term NBW
Maternal race
White
Black
Other
Gender
Male
Female
Maternal age (year)
<25
25–34
≥35
Variable
Total New York State
1.00 Reference
1.03 [0.72, 1.48]
1.42 [0.88, 2.25]
1.01 [0.74, 1.38]
1.00 Reference
1.00 Reference
1.33 [0.94, 1.86]
1.38 [0.78, 2.31]
2.78 [1.69, 4.34]
0.98 [0.41, 1.95]
1.82 [0.89, 3.29]
1.00 Reference
1.15 [0.72, 1.84]
1.37 [0.88, 2.16]
1.00 Reference
1.24 [0.79, 1.96]
aRR [95% CI]
Table 2. Crude and adjusted analyses of isolated/sequence biliary atresia cases by region in New York State, 1983–98
27
51
10
45
43
69
15
4
9
9
7
62
18
17
15
38
n
1.00 Reference
0.95 [0.60, 1.52]
0.93 [0.45, 1.91]
1.10 [0.72, 1.67]
1.00 Reference
1.00 Reference
1.89 [1.08, 3.30]
1.77 [0.65, 4.84]
3.32 [1.65, 6.69]
3.47 [1.72, 6.98]
4.10 [1.88, 8.97]
1.00 Reference
1.35 [0.68, 2.69]
1.16 [0.58, 2.32]
1.00 Reference
2.71 [1.49, 4.93]
RR [95% CI]
1.00 Reference
1.10 [0.69, 1.81]
1.02 [0.47, 2.07]
1.06 [0.70, 1.62]
1.00 Reference
1.00 Reference
1.64 [0.89, 2.84]
1.83 [0.56, 4.41]
3.13 [1.44, 6.01]
3.37 [1.55, 6.45]
3.88 [1.61, 7.95]
1.00 Reference
1.34 [0.67, 2.69]
1.17 [0.58, 2.36]
1.00 Reference
2.64 [1.48, 4.96]
aRR [95% CI]
Other New York State
100
A. R. Caton et al.
© Blackwell Publishing Ltd. Paediatric and Perinatal Epidemiology 2004, 18, 97–105
The epidemiology of extrahepatic biliary atresia in NYS
Figure 1. Three-year moving average
rates of isolated/sequence biliary atresia
by year of birth in New York State
(n = 249), New York City (n = 161), and
other New York State (n = 88), 1983–98.
1.2
1
Rate per 10 000 live births
101
0.8
0.6
0.4
0.2
0
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
Year of birth
New York City
Other New York State
New York State Total
1.2
Rate per 10 000 live births
1
0.8
0.6
0.4
0.2
0
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
NOV
DEC
Month of birth
New York City
Other New York State
regions was greater than at the end of the study period.
The difference was primarily because of an increase in
the number of reported cases from upstate counties.
The rates in the Long Island counties did not vary
significantly during the time frame.
The analyses of season of birth presented in Table 2
and the plot of 3-month moving average rates by
months of birth and conception presented in Fig. 2
show a difference in the seasonal pattern of biliary
atresia by region. The New York City biliary atresia
rate peaked in March births (1.41 per 10 000 live
births), while the other New York State rate peaked in
Figure 2. Three-month moving average
rates of isolated/sequence biliary atresia
by month of birth in New York City
(n = 161) and other New York State
(n = 88), 1983–98.
October births [0.81 per 10 000 live births]. The seasonal pattern is stronger in the other New York State
region than in the New York City region with 43.2% of
other New York State biliary atresia births occurring in
the September–November period. Chi-square analysis
of cases by month of birth resulted in P-values of 0.579
and 0.008 for New York City and other New York State,
respectively. Using the methods of Walter and Elwood
on the New York City month of birth data, the P-value
for the chi-square statistic for centre of gravity was not
significant at 0.441. For month of birth in other New
York State, the P-value for the chi-square statistic for
© Blackwell Publishing Ltd. Paediatric and Perinatal Epidemiology 2004, 18, 97–105
102
A. R. Caton et al.
centre of gravity was significant at <0.001 with a goodness of fit P-value of 0.233, suggesting a poor fit to the
simple harmonic curve.
To control for the effect of preterm delivery, the
methods of Walter and Elwood were applied to the
estimated month of conception data (not shown). In
the New York City data, the P-value for the chi-square
statistic for centre of gravity was borderline significant
at 0.057. The P-value for the chi-square goodness of fit
test was 0.402, suggesting a moderate fit to a simple
harmonic curve. Using the same method on the other
New York State region sample, the P-value for the chisquare statistic for centre of gravity was significant at
0.004 for month of conception, and the P-value for the
chi-square goodness of fit test demonstrates a moderate fit to the simple harmonic curve at 0.410.
Weight for gestational age, race, gender, and
maternal age
Table 2 shows the crude and adjusted rate ratios by
weight for gestational age. In New York State overall,
preterm low-birthweight infants were at highest risk
with an adjusted rate ratio of 2.92 [95% CI 1.94, 4.24]
compared with term normal birthweight infants. In the
crude analysis of race, infants of black mothers in New
York State were at highest risk with a rate ratio of 1.94
[95% CI 1.48, 2.54] when compared with infants of
white mothers, but the rate ratio is reduced to 1.40
[95% CI 1.04, 1.88] in the adjusted analysis (Table 2).
Infants of mothers of other races were also at a significantly higher risk in the unadjusted analysis, but the
results were no longer significant in the adjusted analysis. Infant gender and maternal age were not significant risk factors in either analysis.
Discussion
Case classification and incidence
The incidence of isolated/sequence cases per 10 000
live births in our study, 0.57 [95% CI 0.50, 0.64], is
similar to the incidences found in the two populationbased studies that restricted their analyses to isolated/
sequence cases, 0.63 [95% CI 0.45, 0.81] in Atlanta and
0.47 [95% CI 0.43, 0.51] in France.38,39 The isolated/
sequence cases represented 67% of the total cases of
biliary atresia during the 16-year study period. The
percentage is lower than the 86% found in a metropolitan Atlanta study and the 92% reported from France.
However, Schweizer reported2 that the perinatal form
accounted for approximately 65% of all cases in a series
of surgical patients.
Geographical and seasonal variation
Conflicting results about geographical variation in
biliary atresia incidence exist in the epidemiological
literature. A population-based study in Victoria,
Australia33 reported a significant time-space distribution in urban cases, while a hospital-based study in
north Texas34 found a significantly higher incidence in
rural areas compared with urban areas. French territories had significantly higher rates than France.36,39 On
the other hand, no significant geographical variations
were shown in population-based studies in metropolitan France, Atlanta, or the Netherlands.35,38,39 In our
study, a twofold difference in rates was seen in New
York City infants compared with infants born elsewhere in the state, but the regional difference became
smaller near the end of the study period.
Due to the passive reporting system in New York
State, case ascertainment may have varied by region
and time. New York City area hospitals are known to
under-report anomalies which would make our finding an underestimate of the rate in the New York City
infants.44,45 The increase in reporting from the upstate
hospitals during the study period may reflect an
under-reporting of biliary atresia cases by the less
experienced medical records staff of the upstate hospitals in the earlier years and an increase in case ascertainment in the later years resulting from audits of the
Registry with hospitalisation data.41 To improve case
ascertainment with limited resources, the Registry has
been auditing the completeness of reported malformations since 1993 by comparing the data with the malformations reported to the Statewide Planning and
Research Cooperative System (SPARCS), a mandatory
hospital inpatient and ambulatory surgery database
reported to be 99% comprehensive.46,47 Because surgical intervention is required within the first months of
life, infants with biliary atresia are seen in the hospital
and are likely to be reported to both SPARCS and the
Congenital Malformations Registry. In 1992, there was
a change in the coding scheme from ICD9 codes to BPA
codes. However, since biliary atresia is represented by
one specific code in each scheme, case ascertainment
should not have been affected.41
If the regional differences were not due to reporting
artifacts, the disease variation by maternal residence
© Blackwell Publishing Ltd. Paediatric and Perinatal Epidemiology 2004, 18, 97–105
The epidemiology of extrahepatic biliary atresia in NYS
may be explained by regional differences in population
density, environmental, or socio-economic factors. To
protect confidentiality, the Registry data were provided to us at the county level. A street address or ZIP
code-level analysis would have allowed us to perform
a better time-space analysis including neighbourhoodlevel population density, socio-economic, and environmental variables.
The literature also reports conflicting results for seasonal variation in incidence of biliary atresia. A significantly higher number of cases was seen in the
September to November months in north Texas.34 Significant seasonal clustering in December to March was
found in metropolitan Atlanta using an active-surveillance, population-based registry.38 In Sweden, cases
were unevenly distributed across birth months with
peaks in March and November births.40 Contrary to
these positive associations, seasonal variation in incidence was not supported in the studies in Hawaii, the
Netherlands, Michigan, or metropolitan France.32,35,37,39
The seasonal patterns in New York State varied by
region. The other New York State region showed a
stronger seasonal effect than the New York City area.
Months of birth and conception were both significant
in other New York State region. Although biliary atresia cases may have been under-reported to the Registry, it is unlikely that the bias was differential by month
of birth.
The seasonal variations seen in our study support
an infectious aetiology. In other New York State, 43%
of the cases were born in the September to November
months in the 16-year period. The seasonal pattern in
month of birth with a peak in the cooler months may
be attributed to a viral aetiology. Rotavirus, one of the
suspected viruses used to create animal models, causes
peak infection in cooler months in the United States.48
Despite the weaker seasonal pattern in New York City,
an infectious aetiology cannot be ruled out. There is a
greater chance of coming into contact with an infectious agent in a densely populated area. As more than
one viral agent has been used to create animal models
in the laboratory, more than one infectious agent with
different seasonal patterns may cause the disease.
Small sample sizes in the geographical and seasonality analyses were a limitation in our study and in all
studies. When we restrict our comparisons to the two
studies that attempted to limit analyses to the perinatal
form of the disease, we are left with the studies from
France and metropolitan Atlanta. The metropolitan
Atlanta study, based on 49 cases in a 26-year period,
103
found a non-significant threefold higher rate in Fulton
County, the most densely populated county. The study
also reported significant results for the test of Walter
and Elwood for month of birth. Our regional variation
and seasonality findings are consistent with the
Atlanta study. However, according to Walter and
Elwood,43 seasonality test results should be interpreted
cautiously for samples smaller than 50. Our stratified
analysis of seasonality by geographical region used
samples of 161 and 88 for New York City and other
New York State, respectively. The study in France,
based on 385 cases in an 11-year period, had the most
power to detect geographical and seasonal variations,
and no significant results were demonstrated with the
chi-square and Walter and Elwood tests for seasonality, Knox analysis of time and space-time clusters, nor
the Spearman non-parametric correlation test to assess
the association with urbanisation.
Weight for gestational age, race, gender, and
maternal age
The Hawaii study, based on 20 cases, found a significant relationship between birthweight and biliary
atresia.32 However, no association was seen with
gestational age. The Victoria study, based on 55 cases,
found no association with low birthweight.33 Using
weight for gestational age groups, the metropolitan
Atlanta study found term low-birthweight infants to
be at the highest risk for disease.38 Since the aetiology
of biliary atresia is poorly understood, it is not clear if
term low-birthweight infants are more susceptible to
biliary atresia or if term low birthweight is a result of
the disease. Our results, based on a larger sample,
found significant associations with low birthweight
and preterm birth.
Infants of Chinese fathers in Hawaii had biliary atresia rates five times higher than infants of Caucasian
fathers.32 In the Atlanta study, black infants were at
highest risk in the unadjusted analysis.38 Our analysis
showed black race was still a significant risk factor for
biliary atresia even after controlling for geographical
region and weight for gestational age. Maternal race,
as reported on the birth certificate, may be a proxy for
population density, environmental exposures, or other
socio-economic factors. As in other major malformations, infants of black mothers in New York State are
at higher risk for biliary atresia than those of white
mothers.41 The sample was not large enough to explore
further the relationship with race.
© Blackwell Publishing Ltd. Paediatric and Perinatal Epidemiology 2004, 18, 97–105
104
A. R. Caton et al.
Our non-significant findings for gender are in agreement with other studies that reported results for gender.32,33,36,38 The studies in Hawaii and Victoria showed
an association of biliary atresia with young maternal
age.32,33 As in Atlanta,37 the rate ratios for maternal age
groups were not significant in the New York State data.
Conclusion
Much of the recent laboratory research of biliary atresia has investigated the viral association in humans
and animals, and the pathological findings in biliary
atresia support an infectious aetiology. The association
of isolated/sequence biliary atresia with season, preterm birth, and low birthweight in our study supports
an infectious disease hypothesis. The regional variation should be further explored to determine if the
differences are due to reporting artifacts or true geographical variations.
References
1 Balistreri WF, Grand R, Hoofnagle JH, Suchy FJ, Ryckman FC,
Perlmutter DH, et al. Biliary atresia: current concepts and
research directions. Summary of a symposium. Hepatology
1996; 23:1682–1692.
2 Schweizer P. Treatment of extrahepatic bile duct atresia:
results and long-term prognosis after hepatic
portoenterostomy. Pediatric Surgery International 1986;
1:30–36.
3 Desmet VJ. Congenital diseases of intrahepatic bile ducts:
variation on the theme ‘Ductal Plate Malformation’.
Hepatology 1992; 16:1069–1083.
4 Schreiber RA, Kleinman RE. Genetics, immunology and
biliary atresia: an opening or a diversion? Journal of Pediatric
Gastroenterology and Nutrition 1993; 16:111–113.
5 Fischler B, Ehrnst A, Forsgren M, Orvell C, Nemeth A. The
viral association of neonatal cholestasis in Sweden: a possible
link between cytomegalovirus infection and extrahepatic
biliary atresia. Journal of Pediatric Gastroenterology and
Nutrition 1998; 27:57–64.
6 Tarr PI, Hass JE, Christie DL. Biliary atresia, cytomegalovirus,
and age at referral. Pediatrics 1996; 97:828–831.
7 Chang M-H, Huang H-H, Huang E-S, Kao C-L, Husi H-Y, Lee
C-Y. Polymerase chain reaction to detect human
cytomegalovirus in livers of infants with neonatal hepatitis.
Gastroenterology 1992; 103:1022–1025.
8 Hart MH, Kaufman SS, Vanderhoof JA, Erdman L, Linder J,
Markin RS, et al. Neonatal hepatitis and extrahepatic biliary
atresia associated with cytomegalovirus infection in twins.
American Journal of Diseases of Children 1991; 145:302–305.
9 Stern H, Tucker SM. Cytomegalovirus infection in the
newborn and in early childhood: three atypical cases. Lancet
1965; ii:1268–1271.
10 Jevon GP, Dimmick JE. Biliary atresia and cytomegalovirus
infection: a DNA study. Pediatric and Developmental Pathology
1999; 2:11–14.
11 Witzelben CL, Buck BE, Schnaufer L, Brzosko WJ. Studies of
the pathogenesis of biliary atresia. Laboratory Investigation
1978; 38:525–532.
12 Tyler KL, Sokol RJ, Oberhaus SM, Le M, Karrer FM,
Narkewicz MR, et al. Detection of reovirus RNA in
hepatobiliary tissues from patients with extrahepatic biliary
atresia and choledochal cysts. Hepatology 1998; 27:1475–1482.
13 Richardson SC, Bishop RF, Smith AL. Reovirus serotype 3
infection in infants with extrahepatic biliary atresia or
neonatal hepatitis. Journal of Gastroenterology and Hepatology
1994; 9:264–268.
14 Glaser JH, Balistreri WF, Morecki R. Role of reovirus type 3
in persistent infantile cholestasis. Journal of Pediatrics 1984;
105:912–915.
15 Morecki R, Glaser JH, Johnson AB, Kress Y. Detection of
reovirus type 3 in the porta hepatis of an infant with
extrahepatic biliary atresia: ultrastructural and
immunocytochemical study. Hepatology 1984; 4:1137–1142.
16 Morecki R, Glaser JH, Cho S, Balistreri WF, Horwitz MS.
Biliary atresia and reovirus type 3 infection. New England
Journal of Medicine 1982; 307:481–484.
17 Steele MI, Marshall CM, Lloyd RE, Randolph VE. Reovirus 3
not detected by reverse transcriptase-mediated polymerase
chain reaction analysis of preserved tissue from infants with
choleostatic liver disease. Hepatology 1995; 214:697–702.
18 Brown WR, Sokol RJ, Levin MJ, Silverman A, Tamaru T, Lilly
JR. Lack of correlation between infection with reovirus 3 and
extrahepatic biliary atresia or neonatal hepatitis. Journal of
Pediatrics 1988; 113:670–676.
19 Dussaix E, Hadchouel M, Tardieu M, Alagille D. Biliary
atresia and reovirus type 3 infection. New England Journal of
Medicine 1984; 310:658.
20 Wilson GA, Morrison LA, Fields BN. Association of the
reovirus S1 gene with serotype 3-induced biliary atresia in
mice. Journal of Virology 1994; 68:6458–6465.
21 Parashar K, Tarlow MJ, McCrae MA. Experimental reovirus
type-3 induced murine biliary tract disease. Journal of Pediatric
Surgery 1992; 27:843–847.
22 Papadimitriou JM. The biliary tract in acute murine reovirus
3 infection. American Journal of Pathology 1968; 52:595–601.
23 Stanley NF, Dorman DC, Ponsford J. Studies on the
pathogenesis of a hitherto undescribed virus (hepatoencephalomyelitis) producing unusual symptoms in suckling
mice. Australian Journal of Experimental Biology and Medical
Science 1953; 31:147–160.
24 Riepenhoff-Talty M, Gouvea V, Evans MJ, Svensson L,
Hoffenberg E, Sokol RJ, et al. Detection of group C rotavirus
in infants with extrahepatic biliary atresia. Journal of Infectious
Diseases 1996; 174:8–15.
25 Riepenhoff-Talty M, Gouvea V, Ruffin D, Barrett H, Rossi T.
Group C rotavirus: one possible cause of extrahepatic
biliary atresia in human infants. Pediatric Research 1992;
31:115A.
26 Bobo L, Ojeh C, Chiu D, Machado A, Colombani P, Schwarz
K. Lack of evidence for rotavirus by polymerase chain
reaction/enzyme immunoassay of hepatobiliary samples
© Blackwell Publishing Ltd. Paediatric and Perinatal Epidemiology 2004, 18, 97–105
The epidemiology of extrahepatic biliary atresia in NYS
27
28
29
30
31
32
33
34
35
36
37
from children with biliary atresia. Pediatric Research 1997;
41:229–234.
Petersen C, Biermanns D, Kuske M, Schakel K, MeyerJunghanel L, Mildenberger H. New aspects in a murine
model for extrahepatic biliary atresia. Journal of Pediatric
Surgery 1997; 32:1190–1195.
Petersen C, Bruns E, Kuske M, von Wussow P. Treatment of
extrahepatic biliary atresia with interferon-alpha in a murine
infectious model. Pediatric Research 1997; 42:623–628.
Riepenhoff-Talty M, Shaekel K, Clark HF, Mueller W, Uhnoo
I, Rossi T, et al. Group A rotaviruses produce extrahepatic
biliary obstruction in orally inoculated newborn mice.
Pediatric Research 1993; 33:394–399.
Uhnoo I, Riepenhoff-Talty M, Dharakul T, Chegas P, Fisher
JE, Greenberg HB, et al. Extramucosal spread and
development of hepatitis in immunodeficient and normal
mice infected with rhesus rotavirus. Journal of Virology 1990;
64:361–368.
Czech-Schmidt G, Verhagen W, Szavay P, Leonhardt J,
Petersen C. Immunological gap in the infectious animal
model for biliary atresia. Journal of Surgical Residency 2001;
101:62–67.
Shim WKT, Kasai M, Spence MA. Racial influence on the
incidence of biliary atresia. Progress in Pediatric Surgery 1974;
6:53–62.
Danks DM, Campbell PE, Jack I, Rogers J, Smith AL. Studies
of the aetiology of neonatal hepatitis and biliary atresia.
Archives of Disease in Childhood 1977; 52:360–367.
Strickland AD, Shannon K. Studies in the etiology of
extrahepatic biliary atresia: time-space clustering. Journal of
Pediatrics 1982; 100:749–753.
Houwen RH, Kerremans II, van Steensel-Moll HA, van
Tomunde LK, Bijleveld CM, Schweizer P. Time-space
distribution of extrahepatic biliary atresia in the Netherlands
and West Germany. Zeitschrift Für Kinderchirurgie 1988; 43:68–
71.
Vic P, Gestas P, Mallet EC, Arnaud JP. [Biliary atresia in
French Polynesia. Retrospective study of 10 years]. In French.
Archives de Pédiatrie 1994; 1:646–651.
Ayas MF, Hillemeier AC, Olson AD. Lack of evidence for
seasonal variation in extrahepatic BA during infancy. Journal
of Clinical Gastroenterology 1996; 22:292–294.
105
38 Yoon PW, Bresee JS, Olney RS, James LM, Khoury MJ.
Epidemiology of biliary atresia: a population-based study.
Pediatrics 1997; 99:376–382.
39 Chardot C, Carton M, Spire-Bendelac N, Le Pommelet C,
Golmard JL, Auvert B. Epidemiology of biliary atresia in
France: a national study 1986–96. Journal of Hepatology 1999;
31:1006–1013.
40 Fischler B, Papadogiannakis N, Nemeth A. Aetiological
factors in neonatal cholestasis. Acta Paediatrica Scandinavica
2001; 90:88–92.
41 New York State Department of Health. Congenital
Malformations Registry Annual Report, Statistical Summary of
Children Born in 1995 and Diagnosed Through 1997. New York:
New York State Department of Health, 1999.
42 Kiely JL, Brett KMYuS, Rowley DL. Low birth weight and
intrauterine growth retardation. In: From Data to Action:
CDC’s Public Health Surveillance for Women, Infants, and
Children. Editors: Wilcox LS, Marks JS. Atlanta, GA: US
Department of Health and Human Services, Centers for
Disease Control and Prevention, 1995; pp. 185–202.
43 Walter SD, Elwood JM. A test for seasonality of events with
a variable population at risk. British Journal of Preventive Social
Medicine 1975; 29:18–21.
44 Olsen CL, Polan AK, Cross PK. Case ascertainment for statebased birth defects registries: characteristics of unreported
infants ascertained through birth certificates and their impact
on registry statistics in New York state. Paediatric and Perinatal
Epidemiology 1996; 10:161–174.
45 Forand SP, Talbot TO, Druschel CM, Cross PK. Data quality
and the spatial analysis of disease rates: congenital malformations in New York State. Health and Place 2002; 8:191–199.
46 Druschel C, Sharpe-Stimac M, Cross P. Process of and
problems in changing a birth defects registry reporting
system. Teratology 2001; 64(Suppl. 1):S30–S36.
47 New York State Department of Health. SPARCS Annual Report
1998, Volume 1. New York: New York State Department of
Health, 2000.
48 Jin S, Kilgore PE, Holman RC, Clarke MJ, Gangarosa EJ, Glass
RI. Trends in hospitalizations for diarrhea in United States
children from 1979–1992: estimates of the morbidity
associated with rotavirus. Pediatric Infectious Disease Journal
1996; 15:397–404.
© Blackwell Publishing Ltd. Paediatric and Perinatal Epidemiology 2004, 18, 97–105