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BACKGROUND AND OBJECTIVES: Hirschsprung disease (HSCR) is a congenital defect of the enteric
abstract
nervous system characterized by a lack of ganglion cells in the distal hindgut. The aim of
this study was to assess the birth prevalence, perinatal characteristics, and maternal risk
factors in HSCR patients in Sweden.
METHODS: This was a nationwide, population-based, case-control study of all children born
in Sweden between 1982 and 2012 and registered in the Swedish Medical Birth Register.
Cases were identified in the Swedish National Patient Register and data on potential
maternal risk factors and patient characteristics were collected from the Swedish National
Patient Register and the Swedish Medical Birth Register. Five age- and sex-matched controls
were randomly selected for each case. The association between studied risk factors and
HSCR was analyzed using conditional logistic regression to calculate the odds ratio (OR)
and 95% confidence interval (CI).
RESULTS: The study population comprised 600 HSCR cases and 3000 controls with a male-
to-female ratio of 3.7:1. The birth prevalence of HSCR was 1.91/10000. Maternal obesity
was associated with an increased risk for the child to have HSCR (OR 1.74; CI 1.252.44).
Children with HSCR were born at an earlier gestational age (OR 1.60; CI 1.182.17) than
control children. Associated malformations were identified in 34.5% of the cases.
CONCLUSIONS: This study showed that the Swedish birth prevalence of HSCR was 1.91/10000.
Children with HSCR disease were born at a lower gestational age than controls. Maternal
obesity may increase the risk for the child to have HSCR.
Departments of aWomens and Childrens Health and cLearning, Informatics, Management and Ethics (LIME),
Unit for Medical Statistics, Karolinska Institute, Stockholm, Sweden; and bDivision of Pediatric Surgery, Astrid
Lindgren Childrens Hospital and dCenter of Molecular Medicine, Karolinska University Hospital, Stockholm,
Sweden
Dr Lf Granstrm conceptualized and designed the study, analyzed the data, drafted the article,
and revised the manuscript; Dr Svenningsson and Ms Hagel carried out the initial analyses and
critically reviewed and revised the manuscript; Drs Oddsberg and Nordenskjld conceptualized
and designed the study, acquired the data, and critically reviewed and revised the manuscript;
Dr Wester conceptualized and designed the study, analyzed the data, and critically reviewed and
revised the manuscript; and all authors approved the nal manuscript as submitted.
DOI: 10.1542/peds.2015-4608
ARTICLE
METHODS
Design
This was a nationwide, populationbased case-control study. The study
base includes all neonates born in
Sweden during the observational
period January 1, 1982, to December
31, 2012, and registered in the
Swedish Medical Birth Register
(MBR). The study outcome involved
HSCR and the study exposures being
assessed through linkage with the
Swedish National Patient Register
(NPR) for both cases and their
mothers. All residents in Sweden are
assigned a unique 10-digit personal
identification number after birth or
immigration, which enables linkage
among different national registers.
Registers
The NPR contains prospectively
collected information on all hospital
admissions in Sweden. The register is
maintained by the Swedish National
Board of Health and Welfare. It
was initiated in 1964 and covers all
hospitals in Sweden since 1987. The
data include sex, age, geographic
data, surgical procedures, primary
and secondary diagnoses, and dates
of admission and discharge. The
International Classification of Diseases
(ICD) has been modified over the
years: ICD-8 in 19691986, ICD-9
in 19871996, and ICD-10 since
1997. Since 2001, data on outpatient
specialist care have also been
included in the register. The latest
validation of the register showed that
the diagnoses are valid in 85% to
95% of the cases.12
The MBR contains data on all
pregnancies and deliveries in
Sweden since 1973. The Swedish
National Board of Health and Welfare
administers the register. Correlation
between register data, corresponding
original medical records, and the
validity of the study exposures has
been shown to be excellent.13 The
data are collected prospectively
from antenatal care clinics, obstetric
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LF GRANSTRM et al
Congenital Malformations
FIGURE 1
Flowchart of the study.
Perinatal Characteristics
Exposure data on delivery mode,
gestational age, birth weight, and
neonatal mortality were obtained
from the MBR. Delivery mode was
categorized concerning caesarean
and vaginal delivery. Gestational
age was categorized into 2 groups:
<37 gestational weeks (preterm)
and 37 gestational weeks (term).
Birth weight for gestational age was
categorized into 2 groups according
to Marsl et al: small for gestational
age (SGA) or not, based on growth
curves.15 For the analysis of weight
for gestational age (SGA), twins were
excluded. Data on preeclampsia were
collected from both the MBR and
the NPR, based on the following ICD
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Statistical Analysis
The associations between HSCR
and perinatal characteristics were
examined by using univariable
logistic regression models with
preterm delivery, SGA, and mode
of delivery as the outcomes and
HSCR as an explanatory variable,
presented with odds ratio (OR)
estimates and 95% confidence
intervals (CIs). Possible risk factors
for HSCR (maternal age, maternal
BMI, maternal smoking, and parity)
were analyzed by using a conditional
logistic regression procedure (clogit
in R) stratifying over the matched
pairs. The results were presented
Ethics
The Regional Ethics Review Board
at Karolinska Institutet, Stockholm,
approved the study.
RESULTS
Birth Prevalence
The birth prevalence of HSCR in
Sweden was 1.91 in 10000 births
between 1987 and 2012. The birth
prevalence by sex and the total birth
prevalence over the years are shown
in Fig 2.
Perinatal Characteristics
Of the 600 HSCR cases, 466 were
boys, resulting in a male-to-female
ratio of 3.7:1. There were 19
discordant twins among the cases
and 77 among the controls (OR 1.24,
95% CI 0.752.07). One of the cases
did not survive the first month of life,
and 6 controls died (OR 0.83, 95%
0.106.92). Data on gestational age,
birth weight, and delivery mode are
summarized in Table 3. The data
presented are not causative factors
FIGURE 2
Total birth incidence and male/female birth incidence. The middle lines are a sliding estimate of
average incidence.
DISCUSSION
Congenital Malformations
LF GRANSTRM et al
TABLE 1 Maternal Characteristics With Univariable, Unadjusted ORs With 95% CIs
Maternal age, y
<20
2024
2529
3034
35
Maternal smoking (cigarettes daily)
None
19
10
Missing data
Parity
1
2
3
Maternal BMI
Underweight <18.5
Normal weight 18.524.9
Overweight 25.029.9
Obese 30.0
Missing data
Maternal diseases
Diabetes
Inammatory bowel disease
Multiple sclerosis
Thyroid diseases
a
Cases (n = 600)
Controls (n = 3000)
9
102
203
170
116
68
520
1005
898
509
0.65 (0.321.33)
0.97 (0.751.26)
1
0.94 (0.751.17)
1.13 (0.881.46)
469
62
18
51
2369
277
151
203
1
1.12 (0.831.51)
0.62 (0.381.03)
233
215
152
1249
1100
651
1
1.05 (0.861.28)
1.25 (1.001.56)
9
279
113
57
142
80
1533
514
193
680
0.62 (0.311.26)
1
1.24 (0.961.58)
1.74 (1.252.44)a
11
0
1
26
58
3
3
101
0.95 (0.491.82)
0.6 (0.065.77)
1.3 (0.842.03)
Statistical signicance.
TABLE 2 Subanalysis for Child Sex, Unadjusted ORs With 95% CIs
Maternal age, y
<20
2024
2529
3034
35
Maternal smoking (cigarettes daily)
None
19
10
Missing data
Parity
1
2
3
Maternal BMI
Underweight <18.5
Normal wt 18.524.9
Overweight 25.029.9
Obese 30.0
Missing data
a
Girls
Boys
Cases (n = 134)
Cases (n = 466)
Controls (n = 670)
Controls (n = 2330)
0.96 (0.462.00)
1.00 (0.7421.34)
1
0.97 (0.751.26)
1.20 (0.901.60)
1
1.40 (0.752.63)
0.78 (0.272.28)
66
1
1.05 (0.751.48)
0.59 (0.331.04)
188
1
1.26 (0.831.91)
1.05 (0.641.72)
1
0.99 (0.781.25)
1.30 (1.011.68)a
0.70 (0.202.47)
1
0.80 (0.461.38)
1.03 (0.502.15)
186
0.57 (0.241.35)
1
1.40 (1.051.85)a
2.03 (1.392.96)a
636
Statistical signicance.
TABLE 3 Perinatal Characteristics With Univariable, Unadjusted ORs With 95% CIs
Gestational age, wk
<37
37
Missing data
SGA status
SGA
Not SGA
Missing data
Delivery mode
Caesarean delivery
Vaginal delivery
Missing data
a
Cases
(n=600)
Controls
(n=3000)
60
537
3
196
2793
11
1.60 (1.182.17)a
1
15
557
9
56
2752
97
1.32 (0.742.36)
1
88
493
19
430
2475
95
1.03 (0.801.32)
1
Statistical signicance.
FIGURE 3
Distribution of gestational age for cases and controls. *Signicant difference; OR 1.6, 95% CI 1.182.17.
FIGURE 4
Congenital malformations among the cases. CNS, central nervous system.
LF GRANSTRM et al
CONCLUSIONS
This study shows a stable birth
prevalence of HSCR of 1.91 of 10000
in Sweden. Maternal obesity and
parity may be a risk factor for the
child to develop HSCR and affected
children were born at a lower
gestational age than control subjects.
ABBREVIATIONS
CI:confidence interval
HSCR:Hirschsprung disease
ICD:International Classification of
Diseases
MBR:Swedish Medical Birth
Register
NPR:National Patient Register
OR:odds ratio
SGA:small for gestational age
REFERENCES
1. Moore SW. Congenital anomalies and
genetic associations in Hirschsprungs
disease. In: Holschneider AM, Puri P,
eds. Hirschsprungs Disease and Allied
Disorders. 3rd ed. Berlin, Heidelberg:
Springer Science & Business Media;
2008:115131
2. Best KE, Addor MC, Arriola L, et al.
Hirschsprungs disease prevalence
in Europe: a register based study.
Birth Defects Res A Clin Mol Teratol.
2014;100(9):695702
3. Tam PK, Garcia-Barcel M. Genetic
basis of Hirschsprungs disease.
LF GRANSTRM et al
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