Maternal Risk Factors and

Perinatal Characteristics for

Hirschsprung Disease
Anna Löf Granström, MD,a,b Anna Svenningsson, MD, PhD,a,b Eva Hagel,c Jenny Oddsberg,
MD, PhD,a,b Agneta Nordenskjöld, MD, PhD,a,b,d Tomas Wester, MD, PhDa,b

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 1.91/10 000. Maternal obesity
was associated with an increased risk for the child to have HSCR (OR 1.74; CI 1.25–2.44).
Children with HSCR were born at an earlier gestational age (OR 1.60; CI 1.18–2.17) 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 1.91/10 000.
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 aWomen’s and Children’s Health and cLearning, Informatics, Management and Ethics (LIME),
Unit for Medical Statistics, Karolinska Institute, Stockholm, Sweden; and bDivision of Pediatric Surgery, Astrid
WHAT’S KNOWN ON THIS SUBJECT: Hirschsprung
Lindgren Children’s Hospital and dCenter of Molecular Medicine, Karolinska University Hospital, Stockholm, disease (HSCR) is a multifactorial disease. The
Sweden incidence varies from 1 per 2000 to 1 per 12 000.
Being firstborn may decrease the risk of having the
Dr Löf Granström conceptualized and designed the study, analyzed the data, drafted the article,
disease.
and revised the manuscript; Dr Svenningsson and Ms Hagel carried out the initial analyses and
critically reviewed and revised the manuscript; Drs Oddsberg and Nordenskjöld conceptualized WHAT THIS STUDY ADDS: The incidence of HSCR is
and designed the study, acquired the data, and critically reviewed and revised the manuscript; 1.91 per 10 000 live newborns in Sweden. Maternal
Dr Wester conceptualized and designed the study, analyzed the data, and critically reviewed and obesity increases the risk for having a child with
revised the manuscript; and all authors approved the final manuscript as submitted.
HSCR, and there is increased risk for children with
DOI: 10.1542/peds.2015-4608 HSCR to be born prematurely.
Accepted for publication Apr 20, 2016
Address correspondence to Anna Löf Granström, MD, Division of Pediatric Surgery, Astrid
Lindgren Children’s Hospital, Q3:03, Karolinska University Hospital, Solna, SE-17176 Stockholm.
E-mail: anna.lof@ki.ses To cite: Löf Granström A, Svenningsson A, Hagel E, et al.
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Maternal Risk Factors and Perinatal Characteristics for
Hirschsprung Disease. Pediatrics. 2016;138(1):e20154608

Downloaded from www.aappublications.org/news at University of Antwerp on October 6, 2021

PEDIATRICS Volume 138, number 1, July 2016:e20154608 ARTICLE
Hirschsprung disease (HSCR) is
a congenital defect of the enteric
nervous system characterized by a
lack of ganglion cells in the distal
hindgut. Motility disturbances in the
distal colon usually lead to neonatal
intestinal obstruction. The majority
of the patients undergo surgical
treatment during the first year of
life.
The incidence of HSCR
has been assessed in both
demographic and epidemiologic
studies and varies from 1 in 2000
to 1 in 12 000 live births.1 Best
et al recently reported a slightly
increasing prevalence of HSCR in
Europe.2
HSCR is known to be a multifactorial
disease caused by both genetic
and environmental factors.
Mutations in >10 genes have been
associated with HSCR, particularly
the RET gene, in which 15% to 20%
of patients with isolated HSCR have
mutations.3 Familial occurrence,
male predominance, and the
pattern of associated malformations,
encountered in 4% to 35% of the
cases, also imply a genetic etiology.4
Furthermore, patients with
Down syndrome (trisomy 21)
have a 100-fold risk for HSCR
compared with the normal
population.5 The importance
of environmental factors is not
well known. In a small study of
patients with Down syndrome and
HSCR, extensive coffee drinking
and maternal fever during the
first trimester increased the
risk for HSCR.6 There have been
speculations about the role
of hypothyroidism, vitamin A
deficiency, and maternal intake
of Ibumetin or mycophenolate
during pregnancy, but none of
these associations have been
confirmed.7–11
The purpose of this study was
to investigate the maternal risk
factors and perinatal characteristics
of HSCR in Sweden.
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2 LÖF GRANSTRÖM et al
METHODS
Design
This was a nationwide, population-
based 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 1969–1986, ICD-9
in 1987–1996, 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
clinics, and maternity wards and
include maternal age and parity,
maternal weight and height, maternal
smoking and diseases, duration of
pregnancy, single or multiple birth,
parity, and birth weight.
Cases and Controls
All cases with an ICD code for HSCR
in the Swedish NPR (ICD-8 751.39;
ICD-9 751D; ICD-10 Q431) during
the study period were identified
(n = 816) to confirm that the subjects
had HSCR and were not misclassified
by mistake. For instance, we wanted
to avoid including neonates with
suspected HSCR admitted for rectal
suction biopsies in cases in which the
biopsies turned out to be negative or
patients admitted only to a hospital
without pediatric surgery. Each
case had to satisfy 1 of the following
inclusion criteria:
1. HSCR as the main diagnosis and
a surgical intervention number
specific for HSCR;
2. admission to a pediatric surgical
center at least twice, with a
hospital stay of at least 4 days at
least once, and HSCR as the main
diagnosis for both hospital stays;
and/or
3. One long admission to a pediatric
surgical center once and >1
outpatient visit to a pediatric
surgical center with HSCR as the
main diagnosis.
Using these criteria, 216 patients
were excluded, ending up with 600
HSCR cases; because there were
10 siblings among the cases, 590
mothers were identified. For each
case, 5 controls matched for birth
year and sex and without a history
of HSCR (n = 3000) were randomly
sampled from the study base by
incidence density sampling by using
the RANUNI function in SAS 9.4 (SAS
Institute, Cary, NC). A flowchart is
shown in Fig 1.

FIGURE 1
Flowchart of the study.
Definition and Categorization of
Study Variables
Birth Prevalence
The birth prevalence of HSCR was
assessed by dividing the number of
HSCR cases that met the inclusion
criteria by the number of live
births in Sweden in 1987–2012,
according to the Swedish National
Board of Health and Welfare. The
birth prevalence was also assessed
separately for males and females. We
chose the study period from 1987
instead of 1982 because the NPR
became national in 1987.
Maternal Risk Factors
Exposure data on maternal age,
maternal smoking, parity, and
maternal BMI were obtained from the
MBR. Maternal age was categorized
into 5 groups: <20 years, 20 to 24
years, 25 to 29 years, 30 to 35 years,
and >35 years. Data on maternal
smoking were defined as smoking
at the time of registration at the
antenatal care clinic at gestational
weeks 10 to 12 and were categorized
into nonsmoker, <10 cigarettes
daily, and ≥10 cigarettes daily. Birth
order was categorized into 3 groups;
first, second, and third or greater.
Maternal BMI was measured in
kg/m2 and calculated from the periods
1982 to 1989 and 1992 onward
because of changes in the register.
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PEDIATRICS Volume 138, number 1, July 2016
Maternal BMI was registered at the
first antenatal care clinic visit. BMI
was categorized into 4 groups: <18.5
(underweight), 18.5 to 24.9 (normal
weight), 25.0 to 29.9 (overweight),
and ≥30.0 (obese) according to
the World Health Organization
classification.14
The exposure data on maternal
diseases were based on occurrences
of the following ICD codes: ICD-8:
242, 244, 245, 250, 340.99, 563,
00-563,10; ICD-9: 242, 244, 245, 250,
340A-341×, 555A-X, 556; ICD-10:
E03, E05, E06, E10, E11, E12, E13,
E89, G35.9, K50-51.
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 Marsál 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
codes: ICD 8: 637.00-637.04, 637.09-
637.10, 637.99; ICD 9: 642 E-G;
ICD-10: O14.0-O14.1, O14.9, O11.9.
Neonatal mortality was collected
from the MBR.
Congenital Malformations
Congenital malformations and
chromosomal abnormalities
comprised the following diagnoses
in either the NPR or the MBR: ICD-8:
750.00-759.99; ICD-9: 740-759×;
ICD-10: Q00-Q99. The following
diagnoses were excluded: Meckel
diverticulum (751, 751A, Q430),
undescended testis (752.1, 752F,
Q531-532, Q539), and urachus
remnant (753H, Q644) due to a
diagnostic bias. The malformations
were categorized into the following
categories: gastrointestinal,
cardiovascular, musculoskeletal,
urogenital, ophthalmic, central
nervous system, and other
malformations. The gastrointestinal
malformations were further
analyzed, and cases with only 1
diagnosis from an outpatient visit
or 1 admission to a hospital without
pediatric surgery were excluded.
Data on newborns with Down
syndrome during 1999–2012 were
collected from the Swedish National
Board of Health and Welfare to
assess the cumulative incidence of
HSCR among patients with Down
syndrome.
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
3
with OR and 95% CI. All odds of
HSCR were evaluated by using a
univariable approach. A multivariable
analysis was considered if the
univariable analysis showed that it
was appropriate. All statistics are
performed in R software version
2.38 (http://CRAN.R-project.org/
package=survival).16
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 10 000 births
between 1987 and 2012. The birth
prevalence by sex and the total birth
prevalence over the years are shown
in Fig 2.
Maternal Risk Factors
The maternal risk factors are
summarized in Table 1, and the most
prominent finding was the increased
risk for obese females to have
children with HSCR. There appears
to be a linear increase over BMI
categories; the ORs are not significant
for underweight and overweight, but
this is evident from the effect sizes.
The same gradient effect is shown
in male cases. An analysis using a
multivariate model did not change
the results. A subanalysis of infant
sex is shown in Table 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 0.75–2.07). One of the cases
did not survive the first month of life,
and 6 controls died (OR 0.83, 95%
0.10–6.92). Data on gestational age,
birth weight, and delivery mode are
summarized in Table 3. The data
presented are not causative factors
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4 LÖF GRANSTRÖM et al
FIGURE 2
Total birth incidence and male/female birth incidence. The middle lines are a sliding estimate of
average incidence.
but could instead be associated with
HSCR. The gestational age of cases
and controls is shown in Fig 3. The
odds of HSCR were significantly
greater in preterm compared with
term deliveries in girls (OR 2.69,
95% CI: 1.38–5.26) and in boys (OR:
1.41, 95% CI: 1.00–1.99). The odds
of HSCR for SGA were as follows:
girls, OR 1.59 (95% CI: 0.51–4.97);
boys, OR 1.22 (95% CI: 0.62–2.37).
Preeclampsia occurred as frequently
in mothers of cases as in those of
controls (24 and 95, respectively).
Congenital Malformations
Among the HSCR cases, 207 (34.5%)
individuals had at least 1 other
congenital malformation, including
chromosomal anomalies. Excluding
the cases with only chromosomal
anomalies, 191 of the cases had
associated malformations (Fig 4).
Altogether, 59 (9.8%) of the cases
had Down syndrome and 18 (3%)
had other chromosomal anomalies.
Between 1999 and 2012, 2203
children with Down syndrome were
born in Sweden. Of these, 25 also had
HSCR, which gives a birth prevalence
of 1.1%.
DISCUSSION
This is the first population-based
case-control study including 600
cases of HSCR. The study shows that
the birth prevalence of HSCR was 1
in 5000 in Sweden between 1987
and 2012. We found an association
between HSCR in the child and
maternal obesity during the first
trimester. Also mothers pregnant
with their third child or greater
showed an increased risk of having
a child with HSCR, and patients with
HSCR tended to be born at a lower
gestational age than healthy control
children.
Sweden has well-recognized
population-based medical registers
that make it possible to perform
powerful studies like this one. All
data are prospectively collected,
thus avoiding the risk for recall
bias. The controls were randomly
selected from the study base, thereby
decreasing the risk of selection bias.
Our study assesses a large number
of HSCR cases with cross-linked
data on exposures with the same
definition in cases as in controls.
This methodology decreases the risk
of differential misclassification of
exposure. However, the study also
TABLE 1 Maternal Characteristics With Univariable, Unadjusted ORs With 95% CIs
Cases (n = 600) Controls (n = 3000) Unadjusted OR (95% CI)
Maternal age, y
<20 9 68 0.65 (0.32–1.33)
20–24 102 520 0.97 (0.75–1.26)
25–29 203 1005 1
30–34 170 898 0.94 (0.75–1.17)
≥35 116 509 1.13 (0.88–1.46)
Maternal smoking (cigarettes daily)
None 469 2369 1
1–9 62 277 1.12 (0.83–1.51)
≥10 18 151 0.62 (0.38–1.03)
Missing data 51 203
Parity
1 233 1249 1
2 215 1100 1.05 (0.86–1.28)
≥3 152 651 1.25 (1.00–1.56)
Maternal BMI
Underweight <18.5 9 80 0.62 (0.31–1.26)
Normal weight 18.5–24.9 279 1533 1
Overweight 25.0–29.9 113 514 1.24 (0.96–1.58)
Obese ≥30.0 57 193 1.74 (1.25–2.44)a
Missing data 142 680
Maternal diseases
Diabetes 11 58 0.95 (0.49–1.82)
Inflammatory bowel disease 0 3 —
Multiple sclerosis 1 3 0.6 (0.06–5.77)
Thyroid diseases 26 101 1.3 (0.84–2.03)
a Statistical significance.

has limitations because there was TABLE 2 Subanalysis for Child Sex, Unadjusted ORs With 95% CIs
no histopathology register available Girls Boys
for linkage to confirm the HSCR
Cases (n = 134) Cases (n = 466)
diagnosis. This means that it was
Controls (n = 670) Controls (n = 2330)
necessary to base the diagnosis on
the ICD code, which was the reason Maternal age, y
<20 — 0.96 (0.46–2.00)
for using additional inclusion criteria
20–24 — 1.00 (0.742–1.34)
to increase the specificity of the 25–29 1 1
study. Among the excluded cases, we 30–34 — 0.97 (0.75–1.26)
found that the majority had only been ≥35 — 1.20 (0.90–1.60)
admitted once during the neonatal Maternal smoking (cigarettes daily)
None 1 1
period without having surgery,
1–9 1.40 (0.75–2.63) 1.05 (0.75–1.48)
or admitted to a hospital without ≥10 0.78 (0.27–2.28) 0.59 (0.33–1.04)
pediatric surgery services. Another Missing data 66 188
possible limitation is the risk for type Parity
II errors due to the limited sample 1 1 1
2 1.26 (0.83–1.91) 0.99 (0.78–1.25)
size. Data on HSCR that occurred
≥3 1.05 (0.64–1.72) 1.30 (1.01–1.68)a
in stillbirth or termination for Maternal BMI
fetal anomaly were not possible to Underweight <18.5 0.70 (0.20–2.47) 0.57 (0.24–1.35)
retrieve from the registers and may Normal wt 18.5–24.9 1 1
be a limitation of the study. Overweight 25.0–29.9 0.80 (0.46–1.38) 1.40 (1.05–1.85)a
Obese ≥30.0 1.03 (0.50–2.15) 2.03 (1.39–2.96)a
Our study showed that 1.91 of 10 000 Missing data 186 636
a
or 1 in 5000 live births involved Statistical significance.
HSCR in Sweden from 1987 to 2012.
The birth prevalence did not change although this varies from 1 in 2000 to at risk for HSCR, which includes the
significantly over the study period. 1 in 12 000 live births.1 To calculate number of conceptions that reach
Earlier studies have reported an the incidence, the population at risk the gestational age when the defect
incidence of HSCR of 1 in 5000, is needed. Because the population occurs, is unknown, it is impossible

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PEDIATRICS Volume 138, number 1, July 2016 5
to calculate the incidence. Therefore, TABLE 3 Perinatal Characteristics With Univariable, Unadjusted ORs With 95% CIs
Mason et al recommended calculation Cases Controls Unadjusted OR (95% CI)
of birth prevalence instead. The (n = 600) (n = 3000)
previously published incidence Gestational age, wk
data are comparable to our birth <37 60 196 1.60 (1.18–2.17)a
prevalence data.17 ≥37 537 2793 1
Missing data 3 11
Our results indicate that obesity SGA status
may be a maternal risk factor or at SGA 15 56 1.32 (0.74–2.36)
Not SGA 557 2752 1
least a risk indicator for the child
Missing data 9 97
to have HSCR. It is well known that Delivery mode
prepregnancy obesity is associated Caesarean delivery 88 430 1.03 (0.80–1.32)
with several birth defects, but this Vaginal delivery 493 2475 1
has not been shown specifically Missing data 19 95
for HSCR.18–21 Two known risk a Statistical significance.
factors for birth defects that may
confound this association are blood
folate levels and prepregnancy
diabetes. The blood folate level
among the cases’ mothers is not
available from the registers and
is therefore unknown. The rate
of diabetes among the mothers
was analyzed, and no differences
could be demonstrated between
cases and controls. However,
there is 1 uncommon syndrome,
small left colon syndrome, that
occurs particularly in infants of
diabetic mothers and with an FIGURE 3
unknown etiology.22 The syndrome Distribution of gestational age for cases and controls. *Significant difference; OR 1.6, 95% CI 1.18–2.17.
can simulate HSCR in neonates
within the first 24 to 48 hours of
life, but in our data, there was no
overrepresentation of maternal
diabetes, which makes this an
unlikely explanation.
Untreated hypothyroidism, which
may lead to obesity in the mothers,
could also be considered as a possible
confounder. A case report describing
congenital hypothyroidism associated
with HSCR speculates about the
importance of thyroxin levels and
the development of HSCR.7 Another
speculation may be that obese
mothers have vitamin deficiencies due
to nutritional habits. In mice, vitamin
A deficiency increased the penetrance FIGURE 4
and severity of aganglionosis in Congenital malformations among the cases. CNS, central nervous system.
an experimental model of HSCR.8
Another possible confounder could be
that obese mothers may use medical been suggested in animal models nervous system malformations with
treatments that may increase the that maternal intake of ibuprofen or an HSCR-like pathology, which calls
risk for HSCR in the embryo. It has mycophenolate may cause enteric for studies on maternal intake of drugs

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6 LÖF GRANSTRÖM et al
during pregnancy and the associated
risk for HSCR.9,11
In our study, we found that a parity
of ≥3 children increases the risk
of having a child with HSCR. On
subanalysis for child sex, boys show
the same pattern, but not girls,
perhaps because of the small sample
size and lack of power. This result is
similar to what Ryan et al described,
namely, that being firstborn
decreased the risk for having HSCR.23
Goldberg showed an association
between maternal age and the risk
for HSCR in the offspring, which
could not be confirmed by Best et al
or Russel et al.2,24,25
No correlation could be found
between the risk of having a child
with HSCR and maternal diseases.
Our group previously reported a
family with autosomal dominantly
inherited HSCR associated with
multiple sclerosis. This family
had a novel EDNRB gene mutation
that could potentially play a
role in the development of the
diseases.26 However, in this study,
maternal multiple sclerosis was
not associated with HSCR in the
offspring.
Copyright © 2016 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: This study was supported by the Foundation Frimurare Barnhuset, Her Royal Highness Crown Princess Lovisa Foundation, and the Sällskapet
Barnavård Foundation.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
REFERENCES
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PEDIATRICS Volume 138, number 1, July 2016
We also showed that HSCR patients
were born at a lower gestational
week than controls, thus confirming
earlier studies.23 The prevalence
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systemic review extending from
2000 to 2013 was 4% to 19.4%
(overall prevalence, 14%).27
Preterm birth may have many
causes, for example, preeclampsia
or congenital malformations.
Maternal preeclampsia was not
overrepresented among the cases’
mothers in this study. Another
possible marker for a problematic
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not statistically different between the
groups. Downey et al studied preterm
patients with HSCR and concluded
that they had more associated
anomalies than term patients with
HSCR.28 The rate of associated
malformations reported in this study
(34.5%) is fairly high compared
with other studies. This could be
explained by our broad definition of
malformation: at least 1 diagnosis
in any of the registers, which
could cause an overrepresentation
of the patients with associated
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risk factors and major associated
defects in infants with Down
malformations was found, these
malformations were further
investigated. The birth prevalence
of congenital malformation in the
Swedish general birth population in
2012 was 1.5%; however, that might
be underestimated due to lack of
insufficient validity of that specific
register.29
CONCLUSIONS
This study shows a stable birth
prevalence of HSCR of 1.91 of 10 000
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
syndrome. Epidemiology. 1999;10(3):
264–270
7. Kota SK, Modi KD, Rao MM.
Hirschsprungs disease with congenital
hypothyroidism. Indian Pediatr.
2012;49(3):245–246
8. Fu M, Sato Y, Lyons-Warren A, et al.
Vitamin A facilitates enteric nervous
system precursor migration by
reducing Pten accumulation.
Development. 2010;137(4):631–640
9. Lake JI, Tusheva OA, Graham BL,
Heuckeroth RO. Hirschsprung-like
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Maternal Risk Factors and Perinatal Characteristics for Hirschsprung Disease
Anna Löf Granström, Anna Svenningsson, Eva Hagel, Jenny Oddsberg, Agneta
Nordenskjöld and Tomas Wester
Pediatrics 2016;138;
DOI: 10.1542/peds.2015-4608 originally published online June 15, 2016;

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Maternal Risk Factors and Perinatal Characteristics for Hirschsprung Disease
Anna Löf Granström, Anna Svenningsson, Eva Hagel, Jenny Oddsberg, Agneta
Nordenskjöld and Tomas Wester
Pediatrics 2016;138;
DOI: 10.1542/peds.2015-4608 originally published online June 15, 2016;

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/138/1/e20154608

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
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