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Hirschsprung's disease prevalence in Europe: a register-

based study

Journal: Birth Defects Research Part A: Clinical and Molecular Teratology

Manuscript ID: Draft

Wiley - Manuscript type: Original Research Article

Date Submitted by the Author: n/a

Complete List of Authors: Best, Kate; Newcastle University, UK, Institute of Health & Society Addor, Marie-Claude; Division of Medical Genetics, Arriola, Larraitz; Subdireccion de Salud Publica, Balku, Eszter; National Institute of Health Development, Dept of Hungarian Congenital Abnormality Registry & Surveillance, Barisic, Ingeborg; Children's University Hospital, Bianchi, Fabrizio; CNR Institute of Clinical Physiology, G Monasterio Tuscany Foundation Calzolari, Elisa; Universitaria Ferrara, Azienda Ospedaliero Curran, Rhonda; University of Ulster, Doray, Berenice; Strasbourg Prospective Study of Congenital Malformations, Draper, Elizabeth; University of Leicester, Garne, Ester; Hospital Lillebaelt, Gatt, Miriam; Department of Health Information and research, Haeusler, Martin; Medical University of Graz, van Kammen-Bergman, Jorieke; Department of Medical Genetics, University of Groningen, Khoshnood, Babak; The Paris Registry of Congenital Malformations, Klyungsoyr Melve, Kari; Medical Birth Registry of Norway, Martos, Carmen; Centro Superior de Investigación en Salud Pública, Materna-Kiryluk, Anna; Center for Medical Genetics, Matias Dias, Carlos; Instituto Nacionale de Saude Dr. Ricardo Jorge, McDonnell, Robert; Health Service Executive, Mullaney, Carmel; Health Service Executive, Nelen, Vera; Provinciaal Instituut voor Hygiene, O'Mahony, Mary; Health Service Executive, Queisser-Luft, Annette; Universitatskinderklinik Mainz, Randrianaivo-Ranjatoelina, Hanitra; Naitre Aujourd'hui, Rissman, Anke; Otto-von-Guericke University, Malformation Monitoring Centre Saxony-Anhalt, Medical Faculty Rounding, Catherine; University of oxford, National Perinatal epidemiology Unit Sipek, Antonin; Thomayer University Hospital, Department of Medical Genetics Thompson, Rosie; St Michael's Hospital, Institute of Child Life and Health Tucker, David; Public Health Wales, Wellesley, Diana; Princess Anne Hospital, Wessex Clinical Genetics Service Zymak-Zakutnya, Natalya; OMNI-Net Ukraine Birth Defects Program, Rankin, Judith; Newcastle University, UK, Institute of Health & Society

Key Words: congenital anomaly, congenital aganglionic megacolon, epidemiology,

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prevalence, trends

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Hirschsprung's disease prevalence in Europe: a register based

study

Kate E Best MSc1, Marie-Claude Addor

2,

Larraitz Arriola

3, Eszter Balku

4, Ingeborg

Barisic5, Fabrizio Bianchi

6, Elisa Calzolari

7,

Rhonda Curran

8, Berenice Doray

9, Elizabeth

Draper10

, Ester Garne

11, Miriam Gatt

12, Martin Hauesler

13, Jorieke van Kammen-Bergman

14,

Babak Khoshnood15

, Kari Klungsoyr16

, Carmen Martos17, Anna Materna-Kiryluk18

, Carlos

Matias Dias19

, Bob McDonnell20

, Carmel Mullaney21

, Vera Nela22

, Mary O’Mahony23

,

Anette Queisser-Luft24

, Hanitra Randrianaivo25

, Anke Rissman26

, Catherine Rounding27

,

Antonin Sipek28

, Rosie Thompson29

, David Tucker30

, Diana Wellesley31

, Natalya Zymak-

Zakutnya32

, and Judith Rankin PhD1*

1 Institute of Health & Society, Newcastle University, Newcastle upon Tyne, England, UK.

2 Service de Genetique Medicale Maternite, CHUV, Lausanne, Switzerland

3 Subdireccion de Salud Publica, San Sebastian, Spain

4 Dept of Hungarian Congenital Abnormality Registry and Surveillance, National Institute of

Health Development, Hungary5 Children’s University Hospital of Zagreb, Clinical Hospital

Sisters of Mercy, Zagreb, Croatia

6 Unit of Epidemiology, IFC CNR (Tuscany Registry of Birth Defects), Pisa, Italy

7 IMER Registry (Emila Romagna Registry of Birth Defects),

8 EUROCAT central registry, University of Ulster, Jordanstown.

9 Dept de Genetique Medicale, Hopital de Hautepierre, Strasbourg, France

10 University of Leicester, UK

11 Hospital Lillebaelt, Kolding, Denmark

12 Department of Health Information and Research, Guardamangia, Malta

13 Medical University of Graz, Austria

14 Department of Medical Genetics, University of Groningen, Netherlands

15 Paris Registry of Congenital Malformations, INSERM U953, Paris, France

16 Medical Birth Registry of Norway, Bergen, Norway

17 Centro Superior de Investigación en Salud Pública, Valencia. Spain

18 Polish Registry of Congenital Malformations, Poznan, Poland

19 Centro de Estudos e registo de A C, Av Padre Cruz, Lisbon, Portugal

20 Health Service Executive, Dublin, Ireland

21 Specialist in Public Health Medicine, Public Health Department, HSE South, Lacken,

Kilkenny, Ireland

22 Provincial Institute for Hygiene, Antwerp, Belgium

23 Health Service Executive, Cork, Ireland

24 Birth Registry Mainz Model, Childrens Hospital, University Medical Center, Johannes

Gutenberg-University, Mainz, Germany

25 Naitre Aujhourd'hui, Saint Denis Cedex, Ile de la Reunion

26 Malformation Monitoring Centre Saxony-Anhalt, Medical Faculty Otto-von-Guericke

University, Magdeburg, Germany

27 National Perinatal Epidemiology Unit, University of Oxford, UK

28 National Registry of Congenital Anomalies, Department of Medical Genetics, Thomayer

Hospital, Prague, Czech Republic

29 St Michaels Hospital, Bristol, UK

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30 Public Health Wales, Wales, UK

31 University Hospitals Southampton, Faculty of Medicine and Wessex Clinical Genetics

Service, UK

32 OMNI-Net Ukraine Birth Defects Program, Rivne- Khmelnytskyy, Ukraine

Short title: Hirschsprung's disease in Europe

*Corresponding Author: Prof. Judith Rankin

Address: Institute of Health & Society, Baddiley-Clark Building, Newcastle University,

Newcastle upon Tyne, NE2 4AX, England, UK.

Tel: +44 (0)191 208 5267

Fax: +44 (0)191 222 8211

Email: judith.rankin@ncl.ac.uk

Word count (abstract excluding key words): 250/250

Word count (excluding title page, abstract, references, figures and tables): 2,796

References: 16

ACKNOWLEDGEMENTS

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.

FUNDING

The EUROCAT Joint Action is co-funded by the EC, under the framework of the EU Health

Programme 2008-2013, Grant Agreement 2010 22 04 (Executive Agency for Health &

Consumers). EUROCAT registries are funded as fully described in Paper 6 of Report 9 -

EUROCAT 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 paper reports on an independent study which is part-

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funded by the Policy Research Programme in the Department of Health, UK. The views

expressed are not necessarily those of the Department.

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ABSTRACT 1

Background: 2

Hirschsprung’s disease is a congenital gut motility disorder, characterised by the absence of the 3

enteric ganglion cells along the distal gut. The aim of this study was to describe the 4

epidemiology of Hirschsprung’s disease, including additional congenital anomalies, total 5

prevalence, trends and association with maternal age. 6

Methods: 7

Cases of Hirschsprung’s disease delivered during 1980-2009 notified to 31 European 8

Surveillance of Congenital Anomaly registers formed the population-based case-series. 9

Prevalence rates and 95% confidence intervals (CIs) were calculated as the number of cases per 10

10,000 births. Multilevel Poisson regression was performed to investigate trends in prevalence, 11

geographical variation and the association with maternal age. 12

Results: 13

There were 1,322 cases of Hirschsprung’s disease among 12,146,210 births. The total 14

prevalence was 1.08 (95% CI: 1.03-1.15) per 10,000 births and there was a small but significant 15

increasing trend in prevalence over time (relative risk (RR)= 1.01, 95% Credible interval (CrI): 16

1.00-1.02; p=0.004). There was evidence of geographical heterogeneity in prevalence (p<0.001). 17

Excluding 146 (11.0%) cases with chromosomal anomalies or genetic syndromes, there were 18

1,176 cases (prevalence= 0.97, 95% CI: 0.91-1.03 per 10,000 births), of which 137 (11.6%) had 19

major structural anomalies. There was no evidence of a significant increased risk of 20

Hirschsprung’s disease in cases born to women aged ≥35 years compared to those aged 25-29 21

(RR=1.17, 95% CrI: 1.01-1.35; p=0.355). 22

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Conclusion: 23

This large population-based study found evidence of a small increasing trend in Hirschsprung's 24

disease and differences in prevalence by geographic location. There was also no evidence of an 25

association with maternal age.26

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INTRODUCTION 27

Hirschsprung’s disease (or congenital aganglionic megacolon) is the most common congenital 28

gut motility disorder, characterised by the absence of the enteric ganglion cells (aganglionosis) 29

along the distal gut, which causes functional intestinal obstruction (Puri and Shinkai, 2004). 30

Previous estimates of the live birth prevalence of Hirschsprung’s disease have ranged between 31

1.63 to 2.60 per 10,000 live births in the UK, USA and Columbia (Best et al, 2012; Goldberg, 32

1984; Spouge and Baird, 1985). While a recent study found evidence of a small increasing trend 33

of Hirschsprung's disease prevalence in the North of England, two older studies in the USA and 34

Columbia, did not (Best et al, 2012; Goldberg, 1984; Spouge and Baird, 1985). 35

Hirschprung's disease is of neural crest origin (Martucciello, 1997) and has known associations 36

with a variety of chromosomal anomalies and genetic syndromes, including Down syndrome 37

and Waardenburg syndrome (Amiel et al, 2008; Goldberg, 1984; Moore, 2006; Spouge and 38

Baird, 1985). Therefore, it is considered to be of genetic origin.(Amiel et al, 2008; Badner et al, 39

1990; Martucciello, 1997; Puri and Shinkai, 2004). But despite this possible genetic aetiology, 40

there is limited research around the association with advanced maternal age (Amiel et al, 2008; 41

Badner et al, 1990; Martucciello, 1997; Puri and Shinkai, 2004). In several studies, maternal 42

age has been examined as a potential risk factor, but these studies have only compared the 43

proportion of older mothers in cases with the study population; producing conflicting results. 44

Goldberg (1984) for example, found a higher proportion of mothers aged ≥30 years among cases 45

compared to the general population of Baltimore, USA whereas both Ryan et al (1992) and Best 46

et al (2012) found no significant differences in proportions in Boston, USA and the North of 47

England (Best et al, 2012; Goldberg, 1984; Ryan et al, 1992). Few other risk factors have been 48

identified although there is a suggestion of an association with ethnicity, with the offspring of 49

white women possibly at increased risk (Goldberg, 1984). Additionally, a male preponderance 50

has consistently been reported (Goldberg, 1984; Ryan et al, 1992; Spouge and Baird, 1985). 51

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The aim of this study was to investigate the epidemiology of Hirschsprung's disease in Europe 52

during 1980-2009 using high quality population-based register data. We describe the presence of 53

additional congenital anomalies, pregnancy outcomes, one-week survival, diagnosis, association 54

with maternal age, total prevalence, trends in total prevalence and variation in prevalence 55

according to geographic location.56

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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 collect data on anomalies occurring in spontaneous fetal

losses > 20 weeks gestation, terminations of pregnancy for fetal anomaly following prenatal

diagnosis at any gestation, 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

available 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 01 Jan 1980 and 31 Dec 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 chromosomal anomalies or

genetic syndromes. Cases associated with structural anomalies directly related to Hirschsprung's

disease (e.g. intestinal obstruction or hypoplasia of the large intestine), were classified as

isolated.

Cases from multiple pregnancies were excluded from analysis due to potentially different

aetiologies (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), termination of pregnancy

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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, stillbirth, termination of pregnancy for fetal anomaly or live birth)

and survival beyond one week of age (classed as yes or no). Figures for survival beyond one

week refer to live births only, of which 86% had known survival status.

Multilevel Poisson regression (with two levels) was performed to model total prevalence over

time. The number of cases per year (level 1) were nested within register (level 2) and modelled

with a 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 analysing the model’s change in deviance (using a chi square test on the estimated

difference 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, categorised

as <20, 20-24, 25-29, 30-34 and ≥35) as well as year of delivery. The following registers had

>5% of their maternal age denominator data uncategorised: South Portugal, Saxony Anhalt,

Reunion, Thames Valley, Northern England and Valencia Region and so these registers were

excluded from this analysis 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 registers. There were a further 71 cases with missing maternal age data, which were also

excluded.

Multilevel model parameters were estimated using a random walk (Metropolis-Hastings)

Markov Chain Monte Carlo (MCMC) algorithm. Assuming diffuse uniform priors, the

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procedure was run for a burn-in sample of 5,000 observations, and an analysis sample of

1,000,000 thinned by 10 (numbers guided by Raftery-Lewis calculations) (Raftery and Lewis,

1992). Bayesian 95% Credible Intervals (CrIs), analogous to frequentist 95% CIs, were obtained

from the posterior distribution for each parameter. All models were checked for overdispersion

(by comparing model fit after the addition of another variation term) and trajectories for

parameters and variance were checked to ensure appropriate mixing.

Statistical analyses were performed using Stata version 12, including the runmlwin command.

P<0.05 was considered statistically significant.

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RESULTS

A total of 1,374 cases of Hirschsprung's disease were notified to the 31 EUROCAT registers. Of

these, 33 (2.4%) cases occurring in twin pregnancies and 19 (1.4%) occurring in pregnancies

with unknown number of fetuses were excluded from further analysis (figure 1). Hence, there

were 1,322 singleton cases among a population of 12,146,210 singleton total births between

1980 and 2009.

Additional anomalies

Of the 1,322 singleton cases, 146 (11.0%) occurred with a non-structural anomaly: fifteen

(1.1%) with genetic syndromes (including microdeletions) and 131 (9.9%) with chromosomal

anomalies (figure 1). The most common genetic syndromes were Smith-Lemli-Opitz and

Waardenburg syndrome and the majority (93.9%) of the cases associated with chromosomal

anomalies were Down syndrome (table 1)

Excluding cases with chromosomal anomalies or genetic syndromes, there were 1,176 cases

remaining (figure 1). Of these, 137 (11.6%) were associated with additional major structural

anomalies (table 1) and 1,039 (88.4%) were cases of isolated Hirschsprung's disease.

Sex distribution

There was a male predominance among all cases of Hirschsprung’s disease (73.5% vs 26.2%)

giving a male to female ratio of 2.8:1, which remained the same after excluding cases associated

with chromosomal anomalies or genetic syndromes. The sex ratio of males to females was

slightly higher (2.9: 1) in isolated cases.

Pregnancy outcome

In total, 1,313 (99.3%) of all 1,322 singleton cases resulted in a live birth, two (0.2%) occurred

in late miscarriages and seven (0.5%) cases resulted in termination of pregnancy for fetal

anomaly. Both miscarriages occurred in cases associated with other major structural anomalies.

The terminations of pregnancy were associated with chromosomal anomalies or genetic

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syndromes in three cases, major structural anomalies in two cases and isolated cases in two

cases.

Birth weight and gestational age

Of the 1,313 live born children, the median gestational age at delivery was 39 weeks (IQR: 38-

40), with gestational age missing in 77 (5.9%) cases. Of the live born cases, the mean birth

weight was 3276.5 grams (SD=650.7), with birth weight missing in 256 (19.5%). Of the term

cases (gestational age≥ 37 weeks, n=1103), the mean birth weight was 3389.3g (SD=540.6g)

and of the preterm cases (gestational age<37 weeks, n=125) the mean birth weight was 2278.3g

(SD=688.9g).

Total prevalence

Table 2 shows the number of cases and total prevalence of cases of Hirschsprung's disease by

register. Including all 1,322 singleton cases, the total prevalence was 1.08 (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 (0.01, 0.24) per 10,000 total births in South Portugal (figure 2). There was

a significant difference in prevalence between registers (p<0.001)

Excluding cases associated with chromosomal anomalies or genetic syndromes, the total

prevalence was 0.97 (95% CI: 0.91, 1.03) per 10,000 births, and this varied significantly

between registers (p<0.001).

Trends in prevalence

There was a small but significant increase in Hirschsprung's disease prevalence over the study

period (RR= 1.01, 95% CrI: 1.00, 1.02; p=0.004), which ranged from a modelled 1.04 per

10,000 in 1980-1984 to 1.42 per 10,000 in 2005-2009. There was no evidence that trends over

time varied by register (p=0.203).

Excluding cases associated with chromosomal anomalies or genetic syndromes, there was still

evidence of increasing total prevalence over the study period (RR= 1.01, 95% CrI: 1.00, 1.02;

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p=0.006), which ranged from a modelled 0.93 per 10,000 in 1980-1984 to 1.26 per 10,000 in

2005-2009.

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 to mothers aged 25-29

(RR=1.17, 95% CrI: 1.01, 1.35; p=0.355 ) (table 3). Compared to women aged 25-29, 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 (p<0.001)

and there was still a statistically significant trend over time (RR= 1.01, 95% CrI 1.00, 1.02;

p=0.012).

After excluding cases associated with chromosomal anomalies or genetic syndromes, there were

974 cases. There was no evidence of an association between prevalence 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=1.01, 95% CrI: 1.00, 1.02; p=0.012)

Diagnosis

Time of diagnosis was known in 803 (77.3%) isolated cases. A congenital anomaly was

antenatally detected in 11 (1.4% of 803) cases at a mean gestational age of 31 weeks (inter

quartile 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 one and four weeks in 116 (14.4%) cases, between

one 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 one week survival and eight (0.7%) cases

died in the first week of life. Four of these were isolated cases, two had chromosomal anomalies

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(Down syndrome) and two had other structural anomalies (Prune Belly Sequence and hip

dislocation and/or dysplasia).

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DISCUSSION

This study is the largest to examine the epidemiology of Hirschsprung’s disease. Using data

from 31 European congenital anomaly registers over a period of 30 years, we found a total

prevalence of 1.08 per 10,000 births and a small but significant increase in Hirschsprung’s

disease prevalence over time. We also found a difference in prevalence by geographic

location and no evidence of an association between prevalence and maternal age.

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 organised to deliver care to a

defined population, which allows contributing registers to maximise case ascertainment.

Additionally, this is one of very few studies to investigate prevalence of Hirschsprung’s

disease according to maternal age and to determine the relative risk of Hirschsprung’s disease

in young women and women of advanced maternal age.

We have used advanced methods of analysis to analyse the trends in Hirschsprung’s disease

prevalence over time and the association with maternal age. The multilevel methods utilised

provide more accurate standard error estimates for the nested data than classical approaches

and limit the potential for confounding due to registers contributing 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 investigate the epidemiology of Hirschsprung’s disease both including and

excluding cases with chromosomal anomalies or genetic syndromes which may have

different aetiologies.

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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 improvements in diagnosis and coding over time. Additionally

heterogeneity 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 5-10 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

variables 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 2.60 per 10,000 live births, reported by other studies (Best et al, 2012; Goldberg,

1984; Spouge and Baird, 1985). With Goldberg (1984) reporting a higher prevalence in non-

whites compared to 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 disease, 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

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17

very small, statistically 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-80s 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 Hirschsprung’s disease in cases born to women

aged over 35 when chromosomal anomalies and genetic syndromes were included or

excluded. This corresponds with Best et al’s (2012) findings, where the proportion of mothers

aged over 35 was not significantly greater in cases compared to the general population.

Goldberg (1984) found a significantly greater proportion of cases to mothers aged over 30

compared to 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 investigated before

maternal age is ruled out completely as a risk factor.

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REFERENCES

Amiel J, Sproat-Emison E, Garcia-Barcelo M, Lantieri F, Burzynski G, Borrego S, Pelet A,

Arnold S, Miao X, Griseri P, Brooks AS, Antinolo G, de Pontual L, Clement-Ziza M,

Munnich A, Kashuk C, West K, Wong KK, Lyonnet S, Chakravarti A, Tam PK,

Ceccherini I, Hofstra RM, Fernandez R, Hirschsprung Disease Consortium. 2008.

Hirschsprung disease, associated syndromes and genetics: a review. Journal of

Medical Genetics 45(1):1-14.

Austin PC. 2001. An introduction to multilevel regression models. Canadian Journal of

Public Health 92(2):150-154.

Badner JA, Sieber WK, Garver KL, Chakravarti A. 1990. A genetic study of Hirschsprung

disease. American Journal of Human Genetics 46(3):568-580.

Best KE, Glinianaia SV, Bythell M, Rankin J. 2012. Hirschsprung's disease in the North of

England: Prevalence, associated anomalies, and survival. Birth Defects Research

Part A: Clinical and Molecular Teratology 94(6):477-480.

EUROCAT. 2012a. http://www.eurocat-network.eu/. (Accessed January 2014)

EUROCAT. 2012b. http://www.eurocat-network.eu/aboutus/memberregistries.

(Accessed January 2014)

EUROCAT. 2012c. www.eurocat-network.eu/content/EUROCAT-Guide-1.3.pdf.

(Accessed January 2014)

Glinianaia SV, Rankin J, Wright C. 2008. Congenital anomalies in twins: a register-based

study. Human Reproduction 23(6):1306-1311.

Goldberg EL. 1984. An epidemiological study of Hirschsprung's disease. International

Journal of Epidemiology 13(4):479-485.

Greenlees R, Neville A, Addor MC, Amar E, Arriola L, Bakker M, Barisic I, Boyd PA,

Calzolari E, Doray B. 2011. Paper 6: EUROCAT member registries: organization

and activities. Birth Defects Research Part A: Clinical and Molecular Teratology

91(S1):S51-S100.

Martucciello G. 1997. Hirschsprung's disease as a neurochristopathy. Pediatric Surgery

International 12(1):2-10.

Moore SW. 2006. The contribution of associated congenital anomalies in understanding

Hirschsprung's disease. Pediatric Surgery International 22(4):305-315.

Puri P, Shinkai T. 2004. Pathogenesis of Hirschsprung's disease and its variants: recent

progress. Seminars in Pediatric Surgery 13(1):18-24.

Raftery AE, Lewis S. 1992. How many iterations in the Gibbs sampler. Bayesian Statistics

4(2):763-773.

Ryan ET, Ecker JL, Christakis NA, Folkman J. 1992. Hirschsprung's disease: associated

abnormalities and demography. Journal of Pediatric Surgery 27(1):76-81.

Spouge D, Baird PA. 1985. Hirschsprung disease in a large birth cohort. Teratology

32(2):171-177.

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Table 1: Frequencies of congenital anomalies that occurred in addition to Hirschsprung’s disease*

Chromosomal anomalies

and genetic syndromes,

Group & Subtype

N % of all cases

Chromosomal anomalies

45 X (Turner Syndrome)

Trisomy 2, Mosaicism

Trisomy 7

Trisomy 8 Mosaicism

Trisomy 21 (Down Syndrome)

Deletion of long arm chromosome 13

Other

131

1

1

1

1

123

1

3

9.9

0.1

0.1

0.1

0.1

9.3

0.1

0.2

Genetic Syndromes and Microdeletions

Di George Syndrome

Microdeletion 13

Adams Oliver Syndrome

Mowat Wilson Syndrome

Smith-Lemli-Opitz-Syndome

Marfan Syndrome

Waardenburg Syndrome

15

2

1

1

1

4

1

5

1.1

0.2

0.1

0.1

0.1

0.3

0.1

0.4

Total 146 11.0

Structural anomalies**,

Group & Subtype

N % of all structural

anomalies

Associations

Goldenhar

1

1

0.5

0.5

Sequences

Pierre Robin

Prune Belly

2

1

1

1.0

0.5

0.5

Nervous System 20 9.7

Eye 7 3.4

Congenital heart disease

Ventricular Septal Defect

Atrial Septal Defect

42

17

15

20.4

8.3

7.3

Respiratory System 7 3.4

Oro-facial clefts/palates 8 3.9

Digestive System

Duodenal atresia

Jejunoileal atresia

Ano-rectal anomaly

34

3

6

14

16.5

1.5

2.9

6.8

Abdominal wall defect 3 1.5

Urinary System

Hydronephrosis

Posterior urethral valve

32

15

4

15.5

7.3

1.9

Genital

Hypospadias

13

8

6.3

3.9

Limb

Hip dislocation/ dysplasia

Syndactyly

17

3

4

8.3

1.5

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.

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Table 2: Total prevalence including and excluding cases associated with chromosomal anomalies or genetic syndromes

Register Years

contributed

Total

births Casesa

Prevalence

(95% CI) per

10,000 total

birthsa

Cases

excluding

non-

structural

anomaliesb

Prevalence

(95% CI) per

10,000 total

birthsb

Odense (Denmark) 1980-2009 159594 26 1.63 (1.06, 2.39) 20 1.25 (0.77, 1.94)

Paris (France) 1981-2009 977753 74 0.76 (0.59, 0.95) 69 0.71 (0.55, 0.89)

Tuscany (Italy) 1980-2009 595632 14 0.24 (0.13, 0.39) 13 0.22 (0.12, 0.37)

Dublin (Ireland) 1987-2009 659837 124 1.88 (1.56, 2.24) 102 1.55 (1.26, 1.88)

North Netherlands 1981-2009 479241 73 1.52 (1.19, 1.92) 65 1.36 (1.05, 1.73)

Emilia Romagna (Italy) 1981-2009 789425 30 0.38 (0.26, 0.54) 28 0.36 (0.24, 0.51)

Strasbourg (France) 1982-2007 335962 61 1.82 (1.39, 2.33) 53 1.58 (1.18, 2.06)

Vaud (Switzerland) 1989-2007 157993 25 1.58 (1.02, 2.34) 25 1.58 (1.02, 2.34)

Zagreb (Croatia) 1983-2009 168518 13 0.77 (0.41, 1.32) 13 0.77 (0.41, 1.32)

Malta 1986-2009 111677 31 2.78 (1.89, 3.94) 29 2.6 (1.74, 3.73)

South Portugal 1990-2009 301084 2 0.07 (0.01, 0.24) 2 0.07 (0.01, 0.24)

Antwerp (Belgium) 1990-2009 298827 68 2.28 (1.77, 2.89) 63 2.11 (1.62, 2.7)

Basque Country (Spain) 1990-2009 356578 54 1.51 (1.14, 1.98) 48 1.35 (0.99, 1.79)

Saxony Anhalt (Germany) 1987-2009 318575 21 0.66 (0.41, 1.01) 15 0.47 (0.26, 0.78)

Mainz (Germany) 1990-2009 69179 11 1.59 (0.79, 2.85) 10 1.45 (0.69, 2.66)

Styria (Austria) 1985-2009 296249 56 1.89 (1.43, 2.46) 51 1.72 (1.28, 2.26)

Cork & Kerry (Ireland) 1996-2008ф 99930 18 1.8 (1.07, 2.85) 15 1.50 (0.84, 2.48)

Wales 1998-2009 394394 87 2.21 (1.77, 2.72) 80 2.03 (1.61, 2.52)

Norway 1999-2008 587490 59 1 (0.77, 1.3) 54 0.92 (0.69, 1.2)

Ukraine 2005-2009 146055 12 0.82 (0.43, 1.44) 12 0.82 (0.43, 1.44)

Reunion (France) 2002-2009 117673 28 2.38 (1.58, 3.44) 25 2.13 (1.38, 3.14)

Wielkopolska (Poland) 1999-2009 399014 32 0.8 (0.55, 1.13) 28 0.7 (0.47, 1.01)

Thames Valley (UK) 1996-2009 231041 25 1.08 (0.70, 1.60) 22 1.04 (0.67, 1.55)

Wessex (UK) 1994-2009 429871 68 1.58 (1.23, 2.01) 55 1.28 (0.96, 1.67)

East Midlands & South

Yorkshire (UK)

1998-2009 770634 70 0.91 (0.71, 1.15) 62 0.81 (0.62, 1.03)

Northern England (UK) 2000-2009 314267 57 1.81 (1.37, 2.35) 52 1.66 (1.24, 2.17)

Hungary 1998-2009 1169857 67 0.57 (0.44, 0.73) 62 0.53 (0.41, 0.68)

South East Ireland 1997-2009 85801 11 1.28 (0.64, 2.29) 9 1.05 (0.48, 1.99)

Czech Republic 2000-2009 1029164 67 0.65 (0.51, 0.83) 61 0.59 (0.45, 0.76)

South West England (UK) 2005-2009 239840 25 1.04 (0.68, 1.54) 21 0.88 (0.54, 1.34)

Valencia Region (Spain) 2007 55055 13 2.36 (1.26, 4.04) 12 2.18 (1.13, 3.81)

Total 1980-2009 12146210 1,322 1.08 (1.03, 1.15) 1176 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.

ф Cork and Kerry did not contribute data in 2007

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Table 3: Prevalence according to maternal age category*

Age All cases Excluding non-structural anomalies†

N (%) Prevalence

(95% CI) per

10,000

RR (95% CrI) P-

value

N (%) Prevalence

(95% CI) per

10,000

RR (95% CrI) P-

value

<20 45 (4.1) 0.96 (0.7, 1.29) 0.89 (0.67, 1.2) 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, 1.1) 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

35+ 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 methods, several registers/years were excluded from this analysis.

†Excluding cases occurring with chromosomal anomalies, genetic syndromes or microdeletions

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Flowchart of cases included in the study

164x123mm (220 x 220 DPI)

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Total prevalence of Hirschsprung’s disease by register 164x123mm (220 x 220 DPI)

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