Hirschsprung’s Disease Prevalence in Europe: A Register

Based Study
Kate E. Best1, Marie-Claude Addor2, Larraitz Arriola3, Eszter Balku4, Ingeborg Barisic5,
Fabrizio Bianchi6, Elisa Calzolari7, Rhonda Curran8, Berenice Doray9, Elizabeth Draper10,
Ester Garne11, Miriam Gatt12, Martin Haeusler13, Jorieke van Kammen-Bergman14,
Babak Khoshnood15, Kari Klungsoyr16, Carmen Martos17, Anna Materna-Kiryluk18,
Carlos Matias Dias19, Bob McDonnell20, Carmel Mullaney21, Vera Nelen22,
Mary O’Mahony23, Annette Queisser-Luft24, Hanitra Randrianaivo25, Anke Rissmann26,
Catherine Rounding27, Antonin Sipek28, Rosie Thompson29, David Tucker30,
Diana Wellesley31, Natalya Zymak-Zakutnia32, and Judith Rankin*1

Background: Hirschsprung’s disease is a congenital gut motility disorder,
characterised by the absence of the enteric ganglion cells along the distal gut.
The aim of this study was to describe the epidemiology of Hirschsprung’s
disease, including additional congenital anomalies, total prevalence, trends,
and association with maternal age. Methods: Cases of Hirschsprung’s disease
delivered during 1980 to 2009 notified to 31 European Surveillance of
Congenital Anomaly registers formed the population-based case-series.
Prevalence rates and 95% confidence intervals were calculated as the
number of cases per 10,000 births. Multilevel Poisson regression was
performed to investigate trends in prevalence, geographical variation and the
association with maternal age. Results: There were 1,322 cases of
Hirschsprung’s disease among 12,146,210 births. The total prevalence was
1.09 (95% confidence interval, 1.03–1.15) per 10,000 births and there was a
small but significant increase in prevalence over time (relative risk 5 1.01;
95% credible interval, 1.00–1.02; p 5 0.004). There was evidence of
geographical heterogeneity in prevalence (p < 0.001). Excluding 146 (11.0%)
cases with chromosomal anomalies or genetic syndromes, there were 1,176
cases (prevalence 5 0.97; 95% confidence interval, 0.91–1.03 per 10,000
births), of which 137 (11.6%) had major structural anomalies. There was no
evidence of a significant increased risk of Hirschsprung’s disease in cases
born to women aged 35 years compared with those aged 25 to 29 (relative
risk 5 1.09; 95% credible interval, 0.91–1.31; p 5 0.355). Conclusion: This
large population-based study found evidence of a small increasing trend in
Hirschsprung’s disease and differences in prevalence by geographic location.
There was also no evidence of an association with maternal age.
Birth Defects Research (Part A) 00:000–000, 2014.
C 2014 Wiley Periodicals, Inc.
V
Key words: Hirschsprung’s disease; congenital aganglionic megacolon; gut
motility disorder; prevalence; trends

1 21
Institute of Health & Society, Newcastle University, Newcastle upon Tyne, Specialist in Public Health Medicine, Public Health Department, HSE South,
England, United Kingdom Lacken, Kilkenny, Ireland
2 22
Service de Genetique Medicale Maternite, CHUV, Lausanne, Switzerland Provincial Institute for Hygiene, Antwerp, Belgium
3 23
Subdireccion de Salud Publica, San Sebastian, Spain Health Service Executive, Cork, Ireland
4 24
Department of Hungarian Congenital Abnormality Registry and Surveillance, Birth Registry Mainz Model, Childrens Hospital, University Medical Center,
National Institute of Health Development, Hungary Johannes Gutenberg-University, Mainz, Germany
5 25
Children’s University Hospital of Zagreb, Clinical Hospital Sisters of Mercy, Naitre Aujhourd’hui, Saint Denis Cedex, Ile de la Reunion
Zagreb, Croatia 26
Malformation Monitoring Centre Saxony-Anhalt, Medical Faculty Otto-von-
6
Unit of Epidemiology, IFC CNR (Tuscany Registry of Birth Defects), Pisa, Italy Guericke University, Magdeburg, Germany
7 27
IMER Registry (Emila Romagna Registry of Birth Defects), Ferrara, Italy National Perinatal Epidemiology Unit, University of Oxford, United Kingdom
8 28
EUROCAT central registry, University of Ulster, Northern Ireland, United Kingdom National Registry of Congenital Anomalies, Department of Medical Genetics,
9 Thomayer Hospital, Prague, Czech Republic
Department de Genetique Medicale, Hopital de Hautepierre, Strasbourg,
29
France St Michael’s Hospital, Bristol, United Kingdom
10 30
Department of Health Sciences, University of Leicester, United Kingdom Public Health Wales, Wales, United Kingdom
11 31
Hospital Lillebaelt, Kolding, Denmark University Hospitals Southampton, Faculty of Medicine and Wessex Clinical
12 Genetics Service, United Kingdom
Department of Health Information and Research, Guardamangia, Malta
13 32
Medical University of Graz, Austria OMNI-Net Ukraine Birth Defects Program, Khmelnytskyy Perinatal Center,
14
Department of Medical Genetics, University of Groningen, The Netherlands Ukraine
15
Paris Registry of Congenital Malformations, INSERM U953, Paris, France *Correspondence to: Judith Rankin, Institute of Health & Society, Baddiley-
16
Medical Birth Registry of Norway, Bergen, Norway Clark Building, Newcastle University, Newcastle upon Tyne, NE2 4AX, Eng-
17
Centro Superior de Investigaci on en Salud Pu blica, Valencia, Spain land, UK. E-mail: judith.rankin@ncl.ac.uk
18
Polish Registry of Congenital Malformations, Poznan, Poland
19 Published online 0 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
Centro de Estudos e registo de A C, Av Padre Cruz, Lisbon, Portugal
20
Doi: 10.1002/bdra.23269
Health Service Executive, Dublin, Ireland

C 2014 Wiley Periodicals, Inc.

V
2 HIRSCHSPRUNG’S DISEASE IN EUROPE
Introduction
Hirschsprung’s disease (or congenital aganglionic megaco-
lon) is the most common congenital gut motility disorder,
characterized by the absence of the enteric ganglion cells
(aganglionosis) along the distal gut, which causes func-
tional intestinal obstruction (Puri and Shinkai, 2004).
Previous estimates of the live birth prevalence of
Hirschsprung’s disease have ranged between 1.63 to 2.26
per 10,000 live births in the United Kingdom, United
States, and Columbia (Goldberg, 1984; Spouge and Baird,
1985; Best et al., 2012). While a recent study found evi-
dence of a small increasing trend of Hirschsprung’s dis-
ease prevalence in the North of England, two older studies
in the United States and Columbia, did not (Goldberg,
1984; Spouge and Baird, 1985; Best et al., 2012).
Hirschprung’s disease is of neural crest origin (Martuc-
ciello, 1997) and has known associations with a variety of
chromosomal anomalies and genetic syndromes, including
Down syndrome and Waardenburg syndrome (Goldberg,
1984; Spouge and Baird, 1985; Moore, 2006; Amiel et al.,
2008). Therefore, it is considered to be of genetic origin
(Badner et al., 1990; Martucciello, 1997; Puri and Shinkai,
2004; Amiel et al., 2008). But despite this possible genetic
etiology, there is limited research around the association
with advanced maternal age (Badner et al., 1990; Martuc-
ciello, 1997; Puri and Shinkai, 2004; Amiel et al., 2008). In
several studies, maternal age has been examined as a
potential risk factor, but these studies have only compared
the proportion of older mothers in cases with the study
population; producing conflicting results. Goldberg (1984)
for example, found a higher proportion of mothers aged
30 years among cases compared with the general popu-
lation of Baltimore, Maryland, USA, whereas both Ryan
et al. (1992) and Best et al. (2012) found no significant
differences in proportions in Boston, Massachusetts, USA,
and the North of England (Goldberg, 1984; Ryan et al.,
1992; Best et al., 2012). Few other risk factors have been
identified although there is a suggestion of an association
with ethnicity, with the offspring of white women possibly
at increased risk (Goldberg, 1984). Additionally, a male
preponderance has consistently been reported (Goldberg,
1984; Spouge and Baird, 1985; Ryan et al., 1992).
The aim of this study was to investigate the epidemiol-
ogy of Hirschsprung’s disease in Europe during 1980 to
2009 using high quality population-based register data.
We describe the presence of additional congenital anoma-
lies, pregnancy outcomes, 1-week survival, diagnosis, asso-
ciation with maternal age, total prevalence, trends in total
prevalence and variation in prevalence according to geo-
graphic location.
Materials and Methods
The European Surveillance of Congenital Anomalies
(EUROCAT) (EUROCAT, 2012a) is a collaborative network
of population-based congenital anomaly registers. Thirty-
eight registers in 20 countries use multiple sources to col-
lect data on anomalies occurring in spontaneous fetal
losses  20 weeks gestation, terminations of pregnancy for
fetal anomaly following prenatal diagnosis at any gesta-
tion, and live births. EUROCAT surveys approximately 1.7
million births per year in Europe, representing almost
31% of the European birth population (EUROCAT, 2012b).
Each register has ethical approval to collect data without
patient consent (Greenlees et al., 2011). Cases are coded
using the WHO International Classification of Disease
(ICD) version 9 or 10 and minor anomalies such as skin
tags and tongue tie are excluded; further details are avail-
able in the EUROCAT guide 1.3 (EUROCAT, 2012c).
All cases of Hirschsprung’s disease (ICD 9 code: 751.3
and ICD 10 code: Q431) with a delivery date between Jan-
uary 1, 1980, and December 31, 2009, notified to 31
EUROCAT registers formed this population-based case
series. Denominator and maternal age data were provided
by EUROCAT (EUROCAT, 2012a).
Cases of Hirschsprung’s disease were classified into
three distinct groups: isolated cases, cases with additional
major structural anomalies or cases occurring with chro-
mosomal anomalies or genetic syndromes. Cases associ-
ated with structural anomalies directly related to
Hirschsprung’s disease (e.g., intestinal obstruction or hypo-
plasia of the large intestine), were classified as isolated.
Cases from multiple pregnancies were excluded from
analysis due to potentially different etiologies (Glinianaia
et al., 2008).
STATISTICAL ANALYSIS
Total prevalence rates for Hirschsprung’s disease in each
register were calculated as the number of cases (whether
ending in fetal loss with gestational age > 20 weeks), ter-
mination of pregnancy for fetal anomaly, or live birth) per
10,000 live and stillbirths. 95% confidence intervals (CIs)
were derived from the binomial distribution.
Descriptive statistics were produced for: additional
major congenital anomalies (including chromosomal
anomalies, genetic syndromes and structural anomalies),
sex, pregnancy outcome (classed as late miscarriage, still-
birth, termination of pregnancy for fetal anomaly, or live
birth), timing of diagnosis amongst cases of isolated
Hirschsprung’s disease cases (classed as antenatal diagno-
sis of any congenital anomaly, postnatal diagnosis of
Hirschsprung’s disease: at birth, within the first week,
within the first month, within the first year or after 1
year) and survival beyond 1 week of age (classed as yes
or no). Figures for survival beyond 1 week refer to live
births only, of which 86% had known survival status.
Multilevel Poisson regression (with two levels) was
performed to estimate the relative risk (RR) of Hirschsprung’s
disease over time. The number of cases per year (level 1)
were nested within register (level 2) and modeled with a
BIRTH DEFECTS RESEARCH (PART A) 00:00–00 (2014) 3

random intercept (to better account for variation between

registers), an offset equal to the log of the total births, and
year as a continuous predictor. Heterogeneity between
registers was tested by analyzing the model’s change in
deviance (using a chi square test on the estimated differ-
ence in parameters) between the null model and the model
incorporating the random intercept. Similarly, the models
were also refitted to include additional random effects to
examine inter-regional differences in trends over time.
Random intercept multilevel models were refitted to
include maternal age (in years, categorized as <20, 20–24,
25–29, 30–34, and 35) as well as year of delivery. The fol-
lowing registers had >5% of their maternal age denomina-
tor data uncategorized: South Portugal, Saxony Anhalt,
Reunion, Thames Valley, Northern England, and Valencia
Region and so these registers were excluded from this anal-
FIGURE 1. Flowchart of cases included in the study.
ysis on maternal age. Tuscany and Strasbourg did not have
denominator data from 1995 and 2006 respectively, so
these years were removed from this analysis for these two Excluding cases with chromosomal anomalies or
registers. There were a further 71 cases with missing genetic syndromes, there were 1,176 cases remaining (Fig.
maternal age data, which were also excluded. 1). Of these, 137 (11.6%) were associated with additional
Multilevel model parameters were estimated using a major structural anomalies (Table 1) and 1039 (88.4%)
random walk (Metropolis-Hastings) Markov Chain Monte were cases of isolated Hirschsprung’s disease.
Carlo (MCMC) algorithm. Assuming diffuse uniform priors,
SEX DISTRIBUTION
the procedure was run for a burn-in sample of 5000
There was a male predominance among all cases of
observations, and an analysis sample of 1,000,000 thinned
Hirschsprung’s disease (73.5% vs. 26.2%) giving a male to
by 10 (numbers guided by Raftery-Lewis calculations)
female ratio of 2.8:1, which remained the same after
(Raftery and Lewis, 1992). Bayesian 95% Credible Inter-
excluding cases associated with chromosomal anomalies or
vals (CrIs), analogous to frequentist 95% CIs, were
genetic syndromes. The sex ratio of males to females was
obtained from the posterior distribution for each parame-
slightly higher (2.9:1) in isolated cases.
ter. All models were checked for overdispersion (by com-
paring model fit after the addition of another variation PREGNANCY OUTCOME
term) and trajectories for parameters and variance were
In total, 1,313 (99.3%) of all 1,322 singleton cases resulted
checked to ensure appropriate mixing.
in a live birth, two (0.2%) occurred in late miscarriages and
Statistical analyses were performed using Stata version
seven (0.5%) cases resulted in termination of pregnancy for
12, including the runmlwin command. p < 0.05 was con-
fetal anomaly. Both miscarriages occurred in cases associated
sidered statistically significant.
with other major structural anomalies. The terminations of
pregnancy were associated with chromosomal anomalies or
Results genetic syndromes in three cases, major structural anomalies
A total of 1,374 cases of Hirschsprung’s disease were noti- in two cases and isolated cases in two cases.
fied to the 31 EUROCAT registers. Of these, 33 (2.4%)
cases occurring in twin pregnancies and 19 (1.4%) occur- BIRTH WEIGHT AND GESTATIONAL AGE

ring in pregnancies with unknown number of fetuses were
excluded from further analysis (Fig. 1). Hence, there were
1322 singleton cases among a population of 12,146,210
singleton total births between 1980 and 2009.
ADDITIONAL ANOMALIES
Of the 1,322 singleton cases, 15 (1.1%) occurred with
genetic syndromes (including microdeletions) and 131
(9.9%) occurred with chromosomal anomalies (Fig. 1).
The most common genetic syndromes were Smith-Lemli-
Opitz and Waardenburg syndrome and the majority
(93.9%) of the cases associated with chromosomal anoma-
lies were Down syndrome (Table 1)
Of the 1,313 live born children, the median gestational age
at delivery was 39 weeks (interquartile range, 38–40),
with gestational age missing in 77 (5.9%) cases. Of the
live born cases, the mean birth weight was 3,276.5 grams
(SD 5 650.7), with birth weight missing in 256 (19.5%). Of
the term cases (gestational age  37 weeks, n 5 1,103), the
mean birth weight was 3,389.3g (SD 5 540.6 g) and of the
preterm cases (gestational age < 37 weeks, n 5 125) the
mean birth weight was 2,278.3 g (SD 5 688.9 g).
TOTAL PREVALENCE
Table 2 shows the number of cases and total prevalence of
cases of Hirschsprung’s disease by register. Including all
4 HIRSCHSPRUNG’S DISEASE IN EUROPE
TABLE 1. Frequencies of Congenital Anomalies That Occurred in Addition to
Hirschsprung’s Disease*
Chromosomal anomalies and
genetic syndromes, group and subtype N % of all cases
Chromosomal anomalies 131 9.9
45 X (Turner syndrome) 1 0.1
Trisomy 2, mosaicism 1 0.1
Trisomy 7 1 0.1
Trisomy 8 mosaicism 1 0.1
Trisomy 21 (Down syndrome) 123 9.3
Deletion of long arm chromosome 13 1 0.1
Other 3 0.2
Genetic syndromes and microdeletions 15 1.1
Di George syndrome 2 0.2
Microdeletion 13 1 0.1
Adams Oliver syndrome 1 0.1
Mowat Wilson syndrome 1 0.1
Smith-Lemli-Opitz-syndome 4 0.3
Marfan syndrome 1 0.1
Waardenburg syndrome 5 0.4
Total 146 11.0
Structural anomalies**, N % of all structural
group and subtype anomalies
Associations 1 0.5
Goldenhar 1 0.5
Sequences 2 1.0
Pierre Robin 1 0.5
Prune belly 1 0.5
Nervous system 20 9.7
Eye 7 3.4
Congenital heart disease 42 20.4
Ventricular septal defect 17 8.3
Atrial septal defect 15 7.3
Respiratory system 7 3.4
Oro-facial clefts 8 3.9
Digestive system 34 16.5
Duodenal atresia 3 1.5
Jejunoileal atresia 6 2.9
Ano-rectal anomaly 14 6.8
Abdominal wall defect 3 1.5
Urinary system 32 15.5
Hydronephrosis 15 7.3
Posterior urethral valve 4 1.9
TABLE 1. Continued
Chromosomal anomalies and
genetic syndromes, group and subtype N % of all cases
Genital 13 6.3
Hypospadias 8 3.9
Limb 17 8.3
Hip dislocation/ dysplasia 3 1.5
Syndactyly 4 1.9
Musculo-skeletal 8 3.9
Other 12 5.8
Total 206 100.0
*Cases occurring in multiple pregnancies were excluded.
**Cases occurring with chromosomal anomalies, genetic syndromes,
or microdeletions are excluded. Structural anomalies with n < 3 not
shown.
1,322 singleton cases, the total prevalence was 1.09 (95%
CI, 1.03–1.15) per 10,000 births for all registers combined.
Total prevalence ranged from 2.78 (95% CI, 1.89–3.94) in
Malta to 0.07 (95% CI, 0.01–0.24) per 10,000 total births
in South Portugal (Fig. 2). There was a significant differ-
ence in prevalence between registers (p < 0.001)
Excluding cases associated with chromosomal anoma-
lies or genetic syndromes, the total prevalence was 0.97
(95% CI, 0.91–1.03) per 10,000 births, and this varied sig-
nificantly between registers (p < 0.001).
TRENDS IN PREVALENCE
There was a small but significant increase in Hirsch-
sprung’s disease prevalence over the study period
RR 5 1.01; 95% CrI, 1.00–1.02; p 5 0.004), which ranged
from a modeled 1.04 per 10,000 in 1980 to 1984 to 1.42
per 10,000 in 2005 to 2009. There was no evidence that
trends over time varied by register (p 5 0.203).
Excluding cases associated with chromosomal anoma-
lies or genetic syndromes, there was still evidence of
increasing total prevalence over the study period
(RR 5 1.01; 95% CrI, 1.00–1.02; p 5 0.006), which ranged
from a modeled 0.93 per 10,000 in 1980 to 1984 to 1.26
per 10,000 in 2005 to 2009.
MATERNAL AGE DISTRIBUTION
There were 1,098 (83.1%) cases with available maternal
age and corresponding maternal age denominator data.
The prevalence was greatest among mothers aged 35
but there was no increased risk of Hirschsprung’s disease
in this age group compared with mothers aged 25 to 29
(RR 5 1.09; 95% CrI, 0.91–1.31; p 5 0.355) (Table 3). Com-
pared with women aged 25 to 29, there was no evidence
of an association with maternal age in any other age group
(Table 3). Accounting for maternal age, there was still a
significant difference in prevalence between registers
BIRTH DEFECTS RESEARCH (PART A) 00:00–00 (2014) 5

TABLE 2. Total Prevalence Including and Excluding Cases Associated with Chromosomal Anomalies or Genetic Syndromes

Cases excluding Prevalence

Total Prevalence (95% CI) non-structural (95% CI) per
Register Yearscontributed births Casesa per 10,000 total birthsa anomaliesb 10,000 total birthsb

Odense (Denmark) 1980–2009 159,594 26 1.63 (1.06, 2.39) 20 1.25 (0.77, 1.94)

Paris (France) 1981–2009 977,753 74 0.76 (0.59, 0.95) 69 0.71 (0.55, 0.89)

Tuscany (Italy) 1980–2009 595,632 14 0.24 (0.13, 0.39) 13 0.22 (0.12, 0.37)

Dublin (Ireland) 1987–2009 659,837 124 1.88 (1.56, 2.24) 102 1.55 (1.26, 1.88)

North Netherlands 1981–2009 479,241 73 1.52 (1.19, 1.92) 65 1.36 (1.05, 1.73)

Emilia Romagna (Italy) 1981–2009 789,425 30 0.38 (0.26, 0.54) 28 0.36 (0.24, 0.51)

Strasbourg (France) 1982–2007 335,962 61 1.82 (1.39, 2.33) 53 1.58 (1.18, 2.06)

Vaud (Switzerland) 1989–2007 157,993 25 1.58 (1.02, 2.34) 25 1.58 (1.02, 2.34)

Zagreb (Croatia) 1983–2009 168,518 13 0.77 (0.41, 1.32) 13 0.77 (0.41, 1.32)

Malta 1986–2009 111,677 31 2.78 (1.89, 3.94) 29 2.6 (1.74, 3.73)

South Portugal 1990–2009 301,084 2 0.07 (0.01, 0.24) 2 0.07 (0.01, 0.24)
Antwerp (Belgium) 1990–2009 298,827 68 2.28 (1.77, 2.89) 63 2.11 (1.62, 2.7)

Basque Country (Spain) 1990–2009 356,578 54 1.51 (1.14, 1.98) 48 1.35 (0.99, 1.79)

Saxony Anhalt (Germany) 1987–2009 318,575 21 0.66 (0.41, 1.01) 15 0.47 (0.26, 0.78)

Mainz (Germany) 1990–2009 691,79 11 1.59 (0.79, 2.85) 10 1.45 (0.69, 2.66)

Styria (Austria) 1985–2009 296,249 56 1.89 (1.43, 2.46) 51 1.72 (1.28, 2.26)
c c
Cork & Kerry (Ireland) 1996–2008 99,930 18 1.80 (1.07, 2.85) 15 1.50 (0.84, 2.48)

Wales 1998–2009 394,394 87 2.21 (1.77, 2.72) 80 2.03 (1.61, 2.52)

Norway 1999–2008 587,490 59 1 (0.77, 1.3) 54 0.92 (0.69, 1.2)

Ukraine 2005–2009 146,055 12 0.82 (0.43, 1.44) 12 0.82 (0.43, 1.44)

Reunion (France) 2002–2009 117,673 28 2.38 (1.58, 3.44) 25 2.13 (1.38, 3.14)

Wielkopolska (Poland) 1999–2009 399,014 32 0.80 (0.55, 1.13) 28 0.70 (0.47, 1.01)

Thames Valley (UK) 1996–2009 231,041 25 1.08 (0.70, 1.60) 22 1.04 (0.67, 1.55)

Wessex (UK) 1994–2009 429,871 68 1.58 (1.23, 2.01) 55 1.28 (0.96, 1.67)

East Midlands & South Yorkshire (UK) 1998–2009 770,634 70 0.91 (0.71, 1.15) 62 0.81 (0.62, 1.03)

Northern England (UK) 2000–2009 314,267 57 1.81 (1.37, 2.35) 52 1.66 (1.24, 2.17)

Hungary 1998–2009 1,169,857 67 0.57 (0.44, 0.73) 62 0.53 (0.41, 0.68)

South East Ireland 1997–2009 85,801 11 1.28 (0.64, 2.29) 9 1.05 (0.48, 1.99)

Czech Republic 2000–2009 1,029,164 67 0.65 (0.51, 0.83) 61 0.59 (0.45, 0.76)
South West England (UK) 2005–2009 239,840 25 1.04 (0.68, 1.54) 21 0.88 (0.54, 1.34)

Valencia Region (Spain) 2007 55,055 13 2.36 (1.26, 4.04) 12 2.18 (1.13, 3.81)

Total 1980–2009 12,146,210 1,322 1.09 (1.03, 1.15) 1,176 0.97 (0.91, 1.03)
a
All singleton cases
b
All singleton cases excluding cases occurring with a chromosomal anomaly, genetic syndrome or microdeletion.
c
Cork and Kerry did not contribute data in 2007.

(p < 0.001) and there was still a statistically significant
trend over time (RR 5 1.01; 95% CrI, 1.00–1.02;
p 5 0.012).
After excluding cases associated with chromosomal
anomalies or genetic syndromes, there were 974 cases.
There was no evidence of an association between preva-
lence and maternal age in any age group. There was still
evidence of a significant difference in prevalence between
registers and a small increase in prevalence over time
(RR 5 1.01; 95% CrI, 1.00–1.02; p 5 0.012)
6 HIRSCHSPRUNG’S DISEASE IN EUROPE

FIGURE 2. Total prevalence of Hirschsprung’s disease by register.

DIAGNOSIS
Time of diagnosis was known in 803 (77.3%) isolated
cases. A congenital anomaly was antenatally suspected in
11 (1.4% of 803) isolated cases at a mean gestational age
of 31 weeks (interquartile range, 22–33). Hirschsprung’s
disease was diagnosed at birth in 161 (20.0%) cases, in
the first week in 354 (44.1%) cases, between 1 and 4
weeks in 116 (14.4%) cases, between 1 and 12 months in
95 (11.8%) cases, after 12 months in 25 (3.1%) cases. The
remaining 41 cases were postnatally diagnosed but at an
unknown time.
ONE WEEK SURVIVAL
There were 1,135 (86.4%) live born cases with known 1
week survival and 8 (0.7%) cases died in the first week of
life. Four of these were isolated cases, two had chromo-
somal anomalies (Down syndrome) and two had other
structural anomalies (Prune Belly Sequence and hip dislo-
cation and/or dysplasia).
Discussion
This study is the largest to examine the epidemiology of
Hirschsprung’s disease. Using data from 31 European con-
genital anomaly registers over a period of 30 years, we
found a total prevalence of 1.09 per 10,000 births and a
small but significant increase in Hirschsprung’s disease
prevalence over time. We also found a difference in preva-
lence by geographic location and no evidence of an associ-
ation between prevalence and maternal age.

TABLE 3. Prevalence According to Maternal Age Category

All cases Excluding non-structural anomaliesa

Prevalence(95% CI) Prevalence(95% CI)

Age N (%) per10,000 RR (95% CrI) p Value N (%) per 10,000 RR (95% CrI) p Value

<20 45 (4.1) 0.96 (0.7, 1.29) 0.89 (0.67, 1.20) 0.445 41 (4.2) 0.88 (0.63, 1.19) 0.90 (0.67, 1.22) 0.508

20–24 200 (18.2) 1.05 (0.91, 1.21) 0.93 (0.80, 1.09) 0.380 181 (18.6) 0.95 (0.82, 1.10) 0.96 (0.82, 1.14) 0.666
25–29 340 (31.0) 0.97 (0.87, 1.08) 1.00 (Reference) – 319 (32.8) 0.91 (0.81, 1.02) 1.00 (Reference) –

30–34 317 (28.9) 0.99 (0.88, 1.11) 0.93 (0.79, 1.09) 0.363 279 (28.6) 0.87 (0.77, 0.98) 0.90 (0.76, 1.07) 0.226

351 196 (17.9) 1.17 (1.01, 1.35) 1.09 (0.91, 1.31) 0.355 154 (15.8) 0.92 (0.78, 1.08) 0.94 (0.78, 1.15) 0.563

Year – – 1.01 (1.00, 1.02) 0.012 – – 1.01 (1.00, 1.02) 0.012

Cases occurring in multiple pregnancies were excluded. As stated in the Materials and Methods section, several registers/years were excluded
from this analysis.
a
Excluding cases occurring with chromosomal anomalies, genetic syndromes or microdeletions.
BIRTH DEFECTS RESEARCH (PART A) 00:00–00 (2014)
The primary strength of this study is that it is based on
data derived from established, high quality, population-
based congenital anomaly registers. Standard methods of
identifying and classifying cases across all registers and the
use of multiple sources of notifications ensure high case
ascertainment. The health services in Europe are organized
to deliver care to a defined population, which allows con-
tributing registers to maximize case ascertainment.
Additionally, this is one of very few studies to investi-
gate the prevalence of Hirschsprung’s disease according to
maternal age and to determine the relative risk of Hirsch-
sprung’s disease in young women and women of advanced
maternal age.
We have used advanced methods of analysis to analyze
the trends in Hirschsprung’s disease prevalence over time
and the association with maternal age. The multilevel
methods used provide more accurate standard error esti-
mates for the nested data than classical approaches and
limit the potential for confounding due to registers con-
tributing data from different time points (Austin, 2001).
A further strength of the study is that we had detailed
information on associated anomalies. Thus we could investi-
gate the epidemiology of Hirschsprung’s disease both
including and excluding cases with chromosomal anomalies
or genetic syndromes which may have different etiologies.
However, this study also has some limitations. The
increasing trend in prevalence could be caused by
improved ascertainment due to the registers becoming
more established over the study period or due to improve-
ments in diagnosis and coding over time. Additionally het-
erogeneity in prevalence between registers may be related
to differences in ascertainment, especially as some of the
registers (such as Paris and Emilia Romagna) have been in
existence for almost 30 years whilst others have only been
collecting data for 5 to 10 years. While most registers
include cases diagnosed by age one (and older in some
registers, including registers in the North of England and
Vaud), several only include cases diagnosed in the first
month (e.g., South Portugal register) or first week (e.g.,
Emilia Romagna register) of life. This may be a source of
heterogeneity because Hirschsprung’s disease is not
always picked up in the neonatal period. However, trends
and geographic variation in prevalence may reflect true
differences, perhaps related to differing exposures
between regions. Although we were able to adjust for
maternal age, we did not have access to data on other var-
iables such as ethnicity, which may be associated with
Hirschsprung’s disease prevalence (Goldberg, 1984).
With few cases occurring in terminations of pregnancy,
late miscarriage or stillbirth, it is not too surprising that
our total prevalence was not greater than the live birth
prevalences of 1.63, 1.76, and 2.26 per 10,000 live births,
reported by other studies (Goldberg, 1984; Spouge and
Baird, 1985; Best et al., 2012). With Goldberg (1984)
reporting a higher prevalence in non-whites compared
7
with whites, other factors such as ethnicity may account
for some of the variation between these studies.
This study found a small but significant increasing
trend in the total birth prevalence of Hirschsprung’s dis-
ease, which was similar to that reported in our previous
study, set in the North of England over a similar time
period (1990–2008) (Best et al., 2012). However, this
trend should be interpreted with caution; although our
large sample size enabled us to detect a very small, statis-
tically significant increase in prevalence, this increase may
not be of clinical significance. Goldberg (1984) and Spouge
and Baird (1985) found no evidence of trends over time
between the 1960s to 1980s in Baltimore and British
Columbia, respectively. However, these are smaller studies
which may not have had the power to detect a small
increase in prevalence. Moreover, these are older studies
performed outside of Europe and so the population and
environments may not be easily comparable to our study.
We found no evidence of an increased risk of Hirsch-
sprung’s disease in cases born to women aged over 35
when chromosomal anomalies and genetic syndromes
were included or excluded. This corresponds with the
findings of Best et al. (2012), where the proportion of
mothers aged over 35 was not significantly greater in
cases compared with the general population. Goldberg
(1984) found a significantly greater proportion of cases
born to mothers aged over 30 compared with the general
population but examined only 33 cases, and Ryan et al.
(1992) found no difference in proportions at all. Therefore,
there is little evidence that increased maternal age is a
risk factor for Hirschsprung’s disease despite the anomaly
having a known genetic element. However, there is some
evidence of an interaction with ethnicity, with Goldberg
identifying some association with increased maternal age
in white women but not in non-white women (Goldberg,
1984). This interaction may need to be further investi-
gated before maternal age is ruled out completely as a
risk factor.
Acknowledgments
We thank the many people throughout Europe involved in
providing and processing information, including affected
families, clinicians, health professionals, medical record
clerks, and registry staff. The EUROCAT Joint Action is co-
funded by the EC, under the framework of the EU Health Pro-
gramme 2008 to 2013, Grant Agreement 2010 22 04 (Execu-
tive Agency for Health & Consumers). EUROCAT registries
are funded as fully described in Paper 6 of Report 9 - EURO-
CAT Member Registries: Organization and Activities (Birth
Defects Research (Part A), 91, S51-S100). The responsibility
for the interpretation of data and/or information supplied is
the authors’ alone. This study reports on an independent
study which is part-funded by the Policy Research Pro-
gramme in the Department of Health, UK. The views
expressed are not necessarily those of the Department.
8 HIRSCHSPRUNG’S DISEASE IN EUROPE
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