Yonago Acta medica 1999;42:95–102

Epidemiological Survey on Chronic Inflammatory Bowel Disease Developed during Childhood in Japan, and a Case-Control Study on Nutrition during Infancy
Hirofumi Urashima, Isaku Ohmori* and Kazuo Shiraki
Department of Pediatrics, Faculty of Medicine, Tottori University, Yonago 683-0826 and*Clinic of Pediatrics, Metropolitan Tsukiji Maternity Hospital, Chuo-ku 104-0044, Japan
An epidemiological survey was performed from 1979 to 1993 on Japanese patients whodeveloped ulcerative colitis (UC) or Crohn’s disease (CD) during childhood. A casecontrol study was also conducted concurrently in order to assess whether artificial feeding during infancy (up to 4 months after birth) could be a risk factor for these diseases.
The cumulative number of patients until 1993 was 578 cases for UC (sex ratio, 1.1:1.0)
and 260 cases for CD (sex ratio, 1.4:1.0). There was almost no change in the number of
new cases of UC and CD per year after 1978, showing cases of around 32 (mean ± SD;
32.1 ± 6.8) per year for UC and 16 (15.7 ± 6.3) per year for CD. A case-control study
was performed on 133 cases of UC and 42 cases of CD. The 2 × 2 contingency tables
were prepared to calculate the odds ratio, significance and 95% confidence interval.
Comparison between the group fed exclusively by breast milk or mixed, and the groupfed by artificial (bottle) feeding alone for the development of inflammatory bowel disease,
showed the following results: in UC, the odds ratio was 0.53 and the 95% confidence
interval was 0.31 to 0.89; and in CD, the odds ratio was 0.30 and the 95% confidence interval was 0.13 to 0.70. These results indicated that breast feeding during infancy until postnatal
4 months might decrease the development of chronic inflammatory bowel disease.
Key words: case-control study; Crohn’s disease; feeding during infancy; inflammatory bowel disease;ulcerative colitis

ber of patients during a 15-year period, from 1979
until 1993, was 578 cases for UC and 260 cses forCD.
Here we present the results of our study on
the epidemiological tendency of childhood IBD
development in Japan and the results of aconcurrently conducted case-control study on
feeding during infancy until postnatal 4 months
and the development of IBD.

Ulcerative colitis (UC) and Crohn’s disease(CD), which are referred to as chronic inflammatory bowel disease (IBD), are chronic intestinal inflammatory diseases of which the pathogenesis and pathologic state are still largely unknown. Compared to Western countries, theincidence of IBD is less frequent in Japan. IBD
often develops in adults at the age of around 20
years and therefore, has been regarded as rare in
Japanese children.
Cooperating with the Research Committee
of Inflammatory Bowel Disease of the Ministryof Health and Welfare of Japan, we conducted anationwide epidemiological survey using aquestionnaire from 1979 for the purpose of clarifying the development and substantial state of
IBD in Japanese children. The cumulative num-Materials and Methods

Nationwide epidemiological survey
The survey was conducted by mailing a questionnaire to a total of 344 institutions through-Abbreviations: CD, Crohn’s disease; IBD, inflammatory bowel disease; UC, ulcerative colitis

95

H. Urashima et al.

Table 1. Diagnostic criteria for UC
Answer a and one of the items under b.
aPresent or past history of persistent or recurrent mucous and bloody stool or melena.

b i)

Endoscopy shows 1) fragile rough or granular mucosa with liability of hemorrhage (contact
hemorrhage) and mucous, bloody and purulent secretion on mucousa, and 2) multiple erosions/ulcers
or pseudopolyposis.

ii)

Biopsy shows inflammatory response mainly on the mucosa often with erosion, crypt abscess, bizarre
arrangement of the glands and transformation of the epithelium.

iii) Barium enema shows 1) transformed mucosa whose surface is rough or granular and 2) multiple
erosions/ulcers or 3) pseudopolyposis, sometimes with intestinal stenosis or shortening.
iv) Surgical resection or autopsy shows typical macroscopic and histological findings of UC. However,infectious colitis such as bacillary dysentery, amebic dysentery, and schistosoma japonicum andtuberculous colitis as well as radiation colitis, ischemic colitis and granulomatous colitis must be
excluded.
Note 1. Keep in mind that some patients do not notice blood in their stool.
Note 2. When it is difficult to make a definite diagnosis because of “unclear” findings, the case should beclassified as “suspect”; then a definite diagnosis should be made if distinctive findings are noticed inrecurrent attacks.
UC, ulcerative colitis.

out Japan, including pediatric clinics and pediatric surgical departments at university hospitals, pediatric hospitals and pediatric clinics at
general hospitals with over 390 beds. The questionnaire included questions on the age at onset,
extent of the disease, symptoms and feeding
during infancy.
The subjects of the present survey were
patients aged under 15 years who consulted anyof the above-listed institutions to which thequestionnaire was sent, and were newly diagnosed as having UC or CD according to thediagnostic criteria shown in Table 1 (The Research Committee of Ulcerative Colitis of The
Japanese Ministry of Health and Welfare, Diagnostic Criteria Section, 1975) and Table 2(Crohn’s Disease Study Committee of the Japanese Society of Gastroenteology, 1976), determined by the Specific Disease Intractable
Bowel Disturbance Survey and Research Groupof the Japanese Ministry of Health and Welfare
or the Japanese Society of Gastroenterology
Crohn’s Disease Study Committee.
The survey was conducted annually from1979 to 1993 by mailing a questionnaire inorder to accumulate cases.

Case-control study on feeding during
infancy and the onset of IBD

Patients
IBD children who were diagnosed and reported
from 1978 to 1988 included 334 cases of UC(male; 174, female; 160) and 135 cases of CD(male; 75, female; 60). Among these, those
whose feeding until postnatal 4 months wasrecorded on the questionnaire were studied.
UC: 264 cases (male; 130, female; 134),with a mean age of 10 years and 6 months (range
from 2 months to 15 years and 10 months).
CD: 94 cases (male; 56, female; 38), with amean age of 11 years and 3 months (range from
2 months to 15 years and 9 months).

Controls
Since the number of cases of both UC and CD israther small, the study required 2 controls foreach UC patient and 3 controls for each CD
patient for statistical analysis.
96

Epidemiological survey on IBD

Table 2. Diagnostic criteria of CD
A case having i) to iii) of the following morbid states which fulfill the clinical and pathological conditions for
CD is classified as “suspect.”
A case having i) to iii) plus one out of iv) to vi) is classified as “definite.”
When a case has iv) and two out of i) to iii) however, it can also be regarded as “definite.”
Intestinal tuberculosis, ulcerative colitis, ischemic enteritis/colitis, radiation enteritis/colitis, intestinal Behçet
disease, non-specific intestinal ulcer, non-specific multiple small intestinal ulcer, and acute terminal ileitis
must first be excluded as possible problems.
i)
ii)
iii)
iv)
v)
vi)

Skipping or regional morbidity
Cobble stone appearance or longitudinal ulcer
Full thickness inflammatory reaction (tumor or stenosis)
Non-caseous sarcoid-like granuloma
Fissure or fistula
Affected anal region (intractable ulcer, atypical anal fistula, or anal fissure)

Note 1. This disease is classified according to the affected region. Example: CD of the ileum, CD of theileum and colon, CD of the colon.
Note 2. Regional colitis (grenulomatous colitis) is regarded as CD.
Note 3. Histological examination of the regional lymph nodes is recommended in surgical patients todifferentiate CD from intestinal tuberculosis.
CD, Crohn’s disease.

The hospitals at which the IBD children
were examined or the collaborating institutionsof the Intractable Inflammatory Bowel Disturbance Survey and Research Group of the Japanese Ministry of Health and Welfare were requested to select the controls and to administerthe questionnaire.
They were instructed to choose controls in arandomized manner from healthy individuals or
outpatients excluding chronic disease patients
matched for age, sex and block of birth (allJapan was divided into 7 blocks), because there
are differences in the number of IBD patients
due to sex, age and block of birth (Urashima etal., 1996). The questionnaire was filled out by
selecting one applicable answer from the
below-mentioned i) to iii) concerning feeding
during infancy (until 4 months of age) in eachselected control: i) breast feeding only, ii)
mixed feeding and iii) artificial feeding only.

ed feeding versus artificial feeding only, ii) mixed
feeding or artificial feeding only versus breast
feeding only; the odds ratio and 95% confidence interval were calculated for each group.
Statistical significance was assessed bystatistical volume χ (chi) which is a modification of the square root of chi-square value andthe 95% confidence interval performed by
Miettinen’s test.

Results

Nationwide epidemiological survey
The cumulative number of cases until 1993 was
578 cases for UC and 260 cases for CD. There
was almost no change in the number of newcases of UC and CD per year after 1978 until
1993, showing a number of around 32 cases(mean ± SD; 32.1 ± 6.8) per year for UC andaround 16 cases (15.7 ± 6.3) per year for CD(Figs. 1 and 2). The incidence rate per 100,000
children in the population shows a recent tendency toward an increase; the proportion was

Analysis
For the data analysis, 2 × 2 contingency tables
were prepared for i) breast feeding only or mix97

H. Urashima et al.

Number of UC patients

50
45
40
35
30

0.18 for UC and 0.13 for CD in 1993
according to our survey. The maleto female ratio was 1.1:1.0 for UC
and 1.4:1.0 for CD, showing a slight
predominance for boys in both diseases.
The predominant initial symptoms of UC were diarrhea (58.3%),
bloody stool (47.6%) and abdominal pain (33.9%); pancolitis occurred in the majority of patients. On
the other hand, the predominant initial symptoms of CD were abdominal pain (74.2%), diarrhea (58.9%)
and fever (56.3%) (Figs. 3 and 4).
Most CD patients had a lesion in thelower ileum, transverse colon or ascending colon.

25
20
15
10
5
0
'78 '79 '80 '81 '82 '83 '84 '85 '86 '87 '88 '89 '90 '91 '92 '93

Year

Number of CD patients

Fig. 1. The annual number of UC patients.

40
35
30
25
20
15
10
5
0
'78 '79 '80 '81 '82 '83 '84 '85 '86 '87 '88 '89 '90 '91 '92 '93

Year
Fig. 2. The annual number of CD patients.

AnemiaWeight loss
Fever
Mucosanguineous stool
Abdominal pain
Bloody stool

Fig. 3. The predominant symptomsof UC at onset.

Diarrhea
0

10

20

30

40

50

60

70

80

90

100

70

80

90

100

Percentage

AnemiaBloody stool
Fatigable
Weight loss

Fig. 4. The predominant symptomsof CD at onset.

Fever
Diarrhea
Abdominal pain
0

10

20

30

40

50

60

Percentage

98Epidemiological survey on IBD

Table 3b. The kind of feedings during early
infancy in CD patients and controls

Table 3a. The kind of feedings during early
infancy in UC patients and controls
Number
UC patients Controls

Number
CD patients Controls

Total

Breast feeding
35
93
128
Mixed
61
128
189
Artificial feeding
37
45
82
Total
133
266
399
UC, ulcerative colitis.
Age: mean, 10 years and 4 months; range, 4 months
to 15 years and 3 months.

Total

Breast feeding
10
51
61
Mixed
17
57
74
Artificial feeding
15
18
33
Total
42
126
168
CD, Crohn’s disease.
age: mean, 11 years and 6 months; range, 11 months
to 15 years and 1 month.

Reports on 133 UC cases (male; 66, female; 67)
with 266 controls and 42 CD cases (male; 23,
female; 19) with 126 controls were collected.
The return rate was 48.2% for UC and 44.7%
for CD (Tables 3a and b).

Analysis based on the above reports gave
the following results concerning breast feeding
only or mixed feeding versus artificial feeding
only: in UC, the odds ratio was 0.53, and the
95% confidence interval was 0.31 to 0.89
(Table 4a); and in CD, the odds ratio was 0.30,
and the 95% confidence interval was 0.13 to0.70 (Table 4b).

Table 4a. Analysis of UC

Table 4b. Analysis of CD

Case-control study on feeding during
infancy and onset of IBD

Number
Total
CD
Controls
patients

Number
Total
UC
Controls
patients
Artificial feeding onlyor mixed
Breast feeding only
Total

98
35
133

Odds ratio
95% Confidence interval

1.51
2.46–0.92

173
93
266

271
128
399

Artificial feeding onlyor mixed
Breast feeding only
Total

32
10
42

Odds ratio
95% Confidence interval

2.18
5.19–0.91

Odds ratio
95% Confidence interval
UC, ulcerative colitis.

96
37
133

221
45
266

107
61
168

Number
Total
CD
Controls
patients

Number
Total
UC
Controls
patients
Breast feeding onlyor mixed
Artificial feeding only
Total

75
51
126

Breast feeding onlyor mixed
Artificial feeding only
Total

317
82
399

Odds ratio
95% Confidence interval
CD, Crohn’s disease.

0.53
0.31–0.89

99

27
15
42

108
18
126

0.30
0.13–0.70

135
33
168

H. Urashima et al.

The above analytical results indicated thatbreast feeding during infancy may decrease thedevelopment of UC and CD.

Discussion
UC and CD are chronic intestinal inflammatory
diseases. There are many similarities between
these two diseases which are collectively called
idiopathic inflammatory bowel disease.
Although IBD has been regarded as a rare
pathologic condition in Japan compared with
Western countries, the number of patients withUC or CD increased significantly in adults from1965 to 1970. The annual occurrence of these
diseases in children did not show any significant changes; about 32 cases for UC and about
16 cases for CD. However, the incidence rate
per 100,000 children in the population ofchildren might demonstrate a tendency toward
an increase recently due to a decrease in the
population of children. The possible causes ofsuch an increase may be westernization ofJapanese dietary habits, which is assumed to bea risk factor for developing these diseases,changes in living environments and progress indiagnostic technology.
Similar to adults, the predominant symptoms in children are diarrhea, bloody stool andabdominal pain in the case of UC and abdominal pain and diarrhea in the case of CD. Growth
disturbance is also a characteristic childhood
symptom.
Infection (Bargen, 1924; Crohn et al., 1932;
William and Fradkin, 1937), immune abnormality (Kraft and Kirsner, 1971), hereditary
factors (Asakura et al., 1982; Mitake et al.,1992) and neural and endocrine abnormality(Kubota et al., 1992; Watanabe et al., 1992,
1997) have long been regarded as factors thatare involved in the development of IBD. Recently, the possible roles of monokines, cytokines and macrophages have been drawing attention as being causes of IBD.
Dietary and living habits have also been
considered as causative factors. People whohave milk allergy (Glassman and Newman,

1990), those who eat more bread, margarine,
cheese and ham, and those who eat less vegetables and fruits are considered to have a higher
risk for developing UC. On the other hand, therisk of developing CD is reported to be higher
in people who eat more carbohydrates, especially sugar (Persson et al., 1987). Some reports have suggested that people who eat a large
amount of fast foods, such as hamburgers andfried chicken, are exposed to a higher risk ofdeveloping IBD. With respect to smoking, it isreported that nonsmokers have a higher risk ofdeveloping UC. By contrast, smoking appears
to be a factor causing CD to worsen (Benoni
and Nilsson, 1987).
There are few reports on the dietary and living habits of children in relation to the development of IBD. Gilat and colleagues (1987) conducted a large scale case-control study on thecauses of childhood IBD at 14 institutions in 9
countries, including Western and MiddleEastern countries. Their study failed to demonstrate a significant difference between the patients and controls with respect to the frequency
and period of breast feeding during infancy.
They reported that the type and times of artificial feeding during infancy, the addition ofsugar to milk or artificial feeding and the timingof initiating mixed feeding probably do not play
any role in the onset of IBD (Gilat et al., 1987).
On the other hand, Bergstrand and Heller(1983) reported that artificial feeding is a significant pathogenic factor of CD. Accordingly,
a definitive conclusion has not yet been reached. The case-control study which we conducted
this time showed one result, namely that theincidence of IBD is significantly lower among
breast-fed Japanese children.
In a report on a case-control study similar toours, Kono and colleagues (1993) describedthat artificial feeding during infancy was notconsidered as a risk factor for the developmentof IBD in Japanese adults. This might indicate
a smaller influence of nutrition during infancy
on the development of IBD in adults. From
this, the discrepancy between our results andthose of Gilat and colleagues (1987) may derivefrom the difference in the subject’s age of the100

Epidemiological survey on IBD

start of the disease (under 20 years in Gilat andcolleagues’ population and under 16 years in
our population).
Artificial feeding lacks IgA defense and has
a higher risk of bacterial contamination compared with breast feeding, which facilitates thedevelopment of transient mucosal injury. Mucosal injury causes antigens to be absorbed
more readily in artificial-fed children. As a result, these children are likely to be sensitized bya dietary antigen such as that in milk and often
develop milk allergy, compared with breast-fed
children. Glassman and Newman (1990) reported that patients who had a past history ofmilk allergy during childhood developed IBD ata significantly early stage. Their report may
indicate that the incidence rate of childhood
IBD is higher for artificial-fed children than forbreast-fed children. Furthermore, the growth ofenterobacterium has been considered to differ
between breast-fed and artificial-fed children.
This difference might have some association
with nutrition during infancy and the development of IBD.
The proportion of breast-fed infants is currently increasing in Japan. We intend to pay
further attention to the increase and decrease of
the incidence of childhood IBD.
Acknowledgments: We would like to thank Prof.
Takayuki Nose, Dept. of Public Health and Prof.
Hironaka Kawasaki, Second Dept. of Medicine,
Faculty of Medicine, Tottori University, for theirhelpful criticism and Assc. Prof. Hitoshi Ohshiro,
Dept. of Public Health, Faculty of Medicine, Tottori
University for his kind assistance for data analysis in
this study.
This study was partly supported by a grant from
the Ministry of Health and Welfare, Government ofJapan.

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(Received December 18, 1998, Accepted January 8, 1999)

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