Hirschsprung's Disease in the Preterm Infant:

Implications for Diagnosis and Outcome

KATHERINE J. BAXTER, B.S., AMINA M. BHATIA, M.D.

From the Division of Pdiatrie Surgery, Emory University and Children's Healthcare of Atlanta, Atlanta, Georgia

Hirschsprung's disease (HD), congenital absence of ganglion cells, is considered uncommon in

preterm infants. The aim was to describe the frequency, presentation, and surgical outcomes of
preterm infants with HD. A retrospective cohort study was conducted of all patients diagnosed
with HD from 2002 to 2012 at a single children's hospital. Clinical presentation and surgical
outcomes were obtained for term (37 weeks of gestation or greater) and preterm infants. One
hundred twenty-nine subjects with HD were identified, 24 (19%) preterm and 105 (81%) term.
Preterm infants were more likely to be diagnosed after 30 days of life (66.7 vs 37.1%, P < 0.01;
median age 2.9 vs 0.3 months, P < 0.05) and to have associated major congenital anomalies (45.8 vs
20.0%, P < 0.01). Fewer preterm infants had primary pull-through operations (45.8 vs 76.2%, P <
0.005). Preterm infants were more likely to have an episode of Hirschsprung's-associated
enterocolitis (45.8 us 24.0%, P < 0.05) but were not more likely to die from any cause (8.3 vs 5.8%,
P = 0.64). HD may be more common in preterm infants than previously recognized, and increased
comorbidities in these patients may lead to delayed diagnosis and increased morbidity. HD
should be considered in the preterm infant presenting with a bowel obstruction, especially when
accompanied by associated anomalies.

IRSCHSPRUNG'S DISEASE (HD) is a congenital absence of ganglion cells in the distal bowel, which
extiends varying lengths into the more proximal large
bowel and less commonly into the small bowel.
Hirschsprung's disease commonly presents as neonatal
bowel obstruction with delayed passage of meconium
(DPM), abdominal distension, and bilious emesis. Because of these obstructive signs and symptoms, the
majority of infants with HD are diagnosed within the
first month of life. ' HD has been generally considered
uncommon in preterm infants. Although recent evidence is sparse, previous estimates for the proportion of
children with a history of prematurity among children
with HD range from 3 to 9 per cent.'^- -^ However, because preterm infants frequently have feeding and
stooling difficulties, the classic signs of intestinal obstruction may not be recognized secondary to the effects
of prematurity itself Preterm infants often have complicated medical courses including respiratory failure,
bradycardia, feeding intolerance, and a higher burden of
congenital anomalies.^ DPM is common in the preterm

Presented at the Annual Scientific Meeting and Postgraduate

Course Program, Southeastern Surgical Congress, Jacksonville,
FL, February 9-12, 2013.
Address correspondence and reprint requests to Katherine J.
Baxter, B.S., Medical Student, Pdiatrie Surgery, Emory University,
1424 Tuxworth Circle, Decatur, GA 30033. E-mail: katiej.baxter
gmail.com.

infant with approximately 32 per cent being delayed

past 48 hours.^ Frequent use of orogastric tubes and
parenteral nutrition in preterm infants may blunt the
appearance of distension and emesis. In addition, signs
of a bowel obstruction and/or colitis caused by HD are
difficult to differentiate from necrotizing enterocolitis
(NEC),^ among other causes. Therefore, diagnosis of
HD may be more difficult in the preterm infant, leading
to delay or misdiagnosis of neonatal obstruction.
Delayed diagnosis of HD beyond 1 week after birth
significantly increases the risk of serious complications
in neonatal patients.^ Patients may be at higher risk of
Hirschsprung's-associated enterocolitis (HAEC), which
can progress to sepsis and become life-threatening.
Delayed diagnosis also affects the surgical treatment of
HD.^ These patients are more likely to need an ostomy
as opposed to a primary pull-through as a result of
massive colonie dilation secondary to chronic constipation or scarring and adhesions from HAEC.
We hypothesized that HD is more common in preterm
infants than previously recognized and that diagnosis
is more often delayed in these patients compared with
term infants, resulting in increased morbidity and differential surgical management.
Patients and Methods

A retrospective chart review was conducted for patients diagnosed with HD from lanuary 2002 to January

734

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HIRSCHSPRUNG'S DISEASE IN THE PRETERM INFANT

2012 at Children's Healthcare of Adanta, Egleston

Hospital. Internal Review Board approval was obtained.
Charts were reviewed for demographics, birth history,
presentadon history, surgical treatment, and outcomes.
Term gestadon was defined as greater than or equal to
37 weeks of gestadon. An episode of HAEC was defined using the criteria developed by Pastor et al.'
HAEC was diagnosed if all four of the following were
present: diarrhea or obstipadon, explosive stool on rectal
examination, abdominal distension, and radiographie
evidenee of bowel obstruction. Emergent operation was
defined as an operadon within 24 hours of admission
before confirmation of diagnosis by biopsy. Variables
were eompared between term and preterm infants. The
X^ test of independence was applied to eategorieal variables with greater than five subjects per variable value.
Eisher's exaet test was used to compare proportions with
less than five subjects per cell. The two-sample independent test was used for normally distributed eontinuous variables, and the nonparametric median test
was used for nonnormal condnuous variables. Significance was defined as P < 0.05.
Results
Chart review idendfied 132 subjeets diagnosed with
HD from 2002 to 2012. Three pafients were excluded
from the term and preterm comparison as a result of
missing gestafional age data but were included in the
TABLE 1.

Baxter and Bhatia

735

overall cohort. Among 129 padents with HD with complete gestadonal age informadon, 24 (19%) were preterm
and 105 (81%) were term.
The overall cohort was 81 per cent male (4.28:1 rado)
and the median age at diagnosis was 0.49 months. The
most eommon presendng signs of HD were abdominal
distension (91.5%) and emesis (56.6%). Delayed passage
of meconium was documented in 47.7 per cent of padents. A family history of HD was reported in 5.6 per
cent of cases. A barium enema was posidve for a transidon zone in 62.9 per eent of padents. Associated major
congenital anomalies were found in 24.4 per cent of
padents. The most eommon assoeiated major congenital
anomahes were trisomy 21 in eight (6.1%) patients and
congenital central hypovendlation syndrome (CCHS) in
five (3.8%) padents. Other abdominal anomalies were
found in six padents and included malrotadon, duodenal
atresia, ileal atresia, pyloric stenosis, and gastroschisis.
The most common site of aganglionosis was the sigmoid
colon (31.8%). A primary pull-through operadon was
performed in 70.5 per eent of patients, and the Soave
technique was used in 77.3 per cent of padents. A
postsurgical stricture occurred in three (2.3%) padents
and anastomode leak oecurred in two (1.5%) padents.
Dmographie and presentation data for term and
preterm subjects are shown in Table 1. Preterm infants
had lower 1-minute (6.36 vs 7.60, P ^ 0.014) and
4-minute (7.50 v^ 8.65, P < 0.01) Apgar scores and
were more likely to be intubated as a neonate (50.0 vs

Characteristics of Term and Preterm Infants with Hirschsprung's Disease*

Sex
Male
Female

Term(n = 105)

Preterm (n = 24)

P value

84 (80.0)
21 (20.0)

20 (83.3)
4 (16.7)

0.709

25 (25.5)
62 (63.3)
11 (11.2)
5 (4.9)
38.97
0.33

12(57.1)
3 (14.3)
6 (28.6)
2 (9.5)
33.45
2.88

74
24
7
21

(70.5)
(22.9)
(6.7)
(21.0)

18
2
4
11

63
95
52
1
44
70

(61.8)
(92.2)
(57.8)
(1.0)
(42.3)
(66.7)

9 (37.5)
22(91.7)
11 (73.3)
2 (8.3)
15 (62.5)
12 (50.0)

Rarp

White
Black
Other
Family history of Hirschsprung's
Gestational age at birth (mean in weeks)
Age at diagnosis (median in months)
Transition zone
Rectosigmoid
Long segment colon
Total colon
Congenital anomalies
Presentation
Emesis
Distension
Delayed passage of meconium t
Mass
Constipation
Positive contrast study

(75.0)
(8.3)
(16.7)
(45.8)

< 0.0001 +
0.091
< 0.0001
0.017

o.iiot
0.008
0.031
0.926
0.255
0.120
0.074
0.126

* Data presented as number (percentage) except where otherwise noted.

t All percentages are calculated from nonmissing data. Delayed passage of meconium data were more often missing from the
record of preterm infants than term infants (37.5 v.5 14.7%).
\ P value for the overall x^ test of independence.
In pairwise x^ comparison with Bonferroni correction denotes a significantly larger proportion in that column.

THE AMERICAN SURGEON

736

7.6%, P < 0.0001). Preterm infants were diagnosed

significantly later in life than term infants with a median age at diagnosis of 2.9 months compared with 0.3
months in term infants {P < 0.01) and, similarly, were
more likely to be diagnosed after 30 days of life (66.7
v.y 37.1%, P < 0.01).
Preterm infants were more likely to have associated
major congenital anomalies (45.8 vs 20.0%, P < 0.01).
With respect to the two most common associated anomalies, preterm infants were more likely to have trisomy
21 (16.7 vs 3.8%, P = 0.039) or CCHS (12.5 vs 1.9%,
P = 0.044). All associated congenital anomalies in
term and preterm infants are shown in Table 2. There
was a nonsignificant trend toward more emergent operations in preterm versus term infants (20.0 vs 9.5%,
P = 0.128) and fewer positive barium enema examinadons (50.0 v^' 66.7%, P = 0.104). There was also
a trend toward more frequent total colon aganglionosis
in preterm infants (16.7 vs 5.7%, P = 0.0891).
Fewer preterm infants had primary pull-through
operadons (45.8 vs 76.2%, P < 0.005), but the frequency of permanent stomas was not stadsdcally different between preterm and term infants (12.5 vs 4.8%,
P = 0.37) (Table 3). A total of nine subjects had
permanent stomas: five for total colon aganglionosis,
two for chronic enterocolids, one for fatal perforated
enterocolids, and one for associated pulmonary insufficiency. Twenty-eight subjects had temporary stomas
either separately or as part of their two-stage pullthrough; indicadons included enterocolids (eight), long
segment aganglionosis (six), delayed diagnosis (four),
overly dilated proximal bowel (three), preoperative perforadon (three), meconium peritonids (one), and dusky
appearance of distal anastomosis (one). Preterm infants
were more likely to have an episode of HAEC either preor postoperadvely (45.8 vs 24.0%, P < 0.05) but were
not more likely to die from any cause (8.3 v^' 5.8%,
P = 0.64).
Discussion
Congenital megacolon or HD is one of the most
common causes of neonatal distal bowel obstruction
in the term neonate. However, as a result of their intestinal immaturity, preterm infants are vulnerable to
disorders that are unique to the preterm infant. In preterm infants, the differential for bowel obstruction includes not only funcdonal bowel dysmodlity, but also
mechanical disease processes such as meconium obstruction of prematurity (meconium plug syndrome),
milk curd obstrucdon secondary to high-caloric density
feeds, NEC, and spontaneous intestinal perforation.
Hence, HD is less commonly considered in the differendal diagnosis of preterm intestinal obstruction than
in the term neonate. In this study, we found that HD

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Vol. 79

TABLE 2. Associated Major Congenital Anomalies in Term

and Preterm Infants with Hirschsprung's Disease
Anomaly

Term
(n = 105)

Preterm
(n = 24)

CCHS
Trisomy 21
Other syndromes*
Other genetic anomalies!
Intestinal anomalies i:
Cardiopulmonary anomalies
Renal anomalies||

2(1.9)
4 (3.8)
5 (4.8)
1 (10)
4 (3.8)
7 (6.7)
3 (2.9)

3(12.5)
4 (16.7)
1 (4.2)
0
2 (8.3)
3 (12.5)
0

* Mowat-Wilson (two), Rubenstein-Taybi, cardiofacial cutaneous syndrome, DiGeorge syndrome, Waardenburg syndrome.
t 13q deletion.
t Pyloric stenosis, malrotation/nonrotation (three), duodenal
stenosis, ileal atresia, gastroschisis.
Aortic root dilation, complete arteriovenous canal, ventricular septal defect (four), transposition of great arteries, hypoplastic aortic arch, double outlet right ventricle, hypoplastic
left ventricle, pulmonary vein stenosis, agenesis of left lung.
II Left renal agenesis, hypoplastic right kidney, renal duplication cyst.
CCHS, congenital central hypoventilation syndrome.
TABLE 3. Outcomes of Term and Preterm Infants with
Hirschsprung 's Disease *

Primary pull-through
Permanent stoma
Enterocolitis
Preoperative
Postoperative
Any
Operative
complications!
Mortality

Term
(n = 105)

Preterm
(n = 24)

P Value

80 (76.2)
5 (4.8)

11 (45.8)
3 (12.5)

0.0003
0.367

14(13.7)
14(13.5)
25 (24.0)
2 (1.9)

5
8
11
3

0.381
0.020
0.032
0.045

6 (5.8)

(20.8)
(33.3)
(45.8)
(12.5)

2 (8.3)

0.643

* Hirschsprung's disease-associated enterocolitis defined

based on the criteria developed by Pastor et al."^
t Stricture (three), anastomotic leak (two).

may be more common in preterm infants than previously

recognized. We found that 19 per cent of our cohort was
preterm infants of less than 37 weeks of gestadon.
As expected, in our study, preterm infants had lower
Apgar scores and were more likely to be intubated as
neonates. Overall complexity of a preterm infant's condidon and the intensity of their care may contribute to the
delay in diagnosis of HD. Other complications of prematurity are numerous but include feeding and stooling
difficulty as well as other abdominal disease processes
such as NEC, intestinal atresia, and meconium plug
syndrome that overlap in presentation with and may
be difficult to disdnguish from HD.''- ' '
Associated congenital anomalies also increase the
complexity of an infant's presentation, ' ^ but if condidons
associated with HD are recognized, they may instead
help to expedite a diagnosis. The overall percentage of
subjects with associated major anomalies in our study
(24.4%) was consistent with previous studies ranging

No. 7

HIRSCHSPRUNG'S DISEASE IN THE PRETERM INFANT

from 11 to 32 per cent with an average of 21 per cent.'^

The increased prevalence of anomalies among preterm
infants (45.8%) in our study is similar to the 47 per
cent found by Klein et al. in 1993^ but appears to be the
first fime this finding is supported by stafisfical tesfing.
Idenfiftcation and epidemiology of associated anomalies with HD impacts diagnosis in both term and preterm infants and may lead to clues in the pathogenesis
of HD.
The association of HD with other neurocristopathies
such as CCHS (Haddad syndrome) is well recognized,
and the genefic locus at PH0X2B has been idenfified,
but this rare syndrome has not been previously associated with preterm birth except in a case report."^' '"* '^
Down syndrome (DS) or trisomy 21 is also known to
be associated with HD, and in fact, the incidence of DS
in pafients with HD may be increasing. Our overall
prevalence of DS was 6.2 per cent, which is shghfiy
lower than previous reports of 8 to 13 per cent, ' ^ ' ^ but
among preterm infants, it was significantly higher at
16.7 per cent. Although reports differ on whether DS is
associated with worse outcomes in HD, DS has been
associated with increased HAEC,'^- '^ and this may
parfially explain our finding of increased morbidity in
the preterm group. The associafion in our cohort of DS
and HD with prematurity has not been previously described. Mowat-Wilson syndrome, found in two subjects in this study, is a rare condition characterized by
dysmorphic features, intellectual disability, and the
presence of HD, most often caused by a de novo mutafion of the gene ZEB2?^ Associafion of RubensteinTaybi syndrome with HD was described in a case report
but appears to be quite rare.^' Our results also agree
with previous reports of an associafion of HD with other
gastrointestinal tract anomalies (chiefiy malrotation and
intestinal atresia), which may provide clues to the etiology of HD through common developmental signaling

Baxter and Bhatia

737

pathways.''' ^^

Despite the prevaiUng belief that HD is uncommon

in preterm infants, there is a paucity of evidence on the
subject. The prevalence of preterm infants in our HD
case series is quite high compared with previous reports, which have ranged from 3 to 9 per cent,^' 2'*' ^^
although most of these case series were limited by
sample size (n less than 35) and were published before
more recent advances in the care of preterm infants. In
the largest case series to report on preterm prevalence
to our knowledge, Klein et al.^ found 8 per cent
preterm infants in 250 patients with HD. Possible contributing factors to our much higher preterm prevalence
are the increased incidence of prematurity over fime^^
and improved diagnostic tesfing for HD. Additionally,
the single-institution nature of this study, its terfiary
referral status, and large Level III neonatal intensive
care unit is an important potential bias. Although we
cannot comment on incidence in this retrospective study,
it is interesting to note that the most recent estimate of
the preterm birth rate in the United States is 12.3 per cent
of all births,^^ and when compared with the rate among
pafients with HD in this study of 19 per cent, this suggests that HD is in fact associated with prematurity.
Further studies are needed to investigate the incidence
of HD in preterm infants, but our study suggests that it
is higher than previously thought and that there are
important implications of delayed diagnosis in these
complicated pafients.
In conclusion, we present novel evidence that HD is
relatively frequently associated with prematurity and
that preterm patients with HD have significant morbidities in the form of delayed diagnosis and increased
incidence of HAEC. Associated comorbidifies are more
common in preterm infants with HD, including CCHS,
trisomy 21, and intesfinal anomalies. HD should be
considered in the preterm infant presenfing with a neonatal bowel obstruction, especially when accompanied
by associated anomalies.

Recent trends in the treatment of HD, including more

frequent use of primary puU-through and predominance
of the Soave endorectal technique,^^ are consistent with
our institution's experience and agree with other recent
HD case series.'- '^ The reasons for fewer primary operafions in preterm infants with HD are unclear. It seems
hkely that this different treatment strategy is related to
delayed diagnosis, increased comorbidities, greater prevalence of HAEC, and possibly greater extent of aganghonosis in preterm patients. Comphcations of delayed
diagnosis in HD were examined by Lee et al.,^ and their
findings of increased HAEC agreed with ours despite
differences in the length of delay and definition of HAEC
used. Future studies are needed to examine whether
early diagnosis would ameliorate this increased morbidity or if it is driven by prematurity itself and associated comphcations.

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