Breastfeeding and risk of inflammatory bowel disease: a systematic review with meta-analysis

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Abstract
It has long been believed that breastfeeding provides protection against ulcerative colitis and Crohn disease. Studies designated to test this hypothesis were conducted without reaching conclusive results. The aim of this meta-analysis was to examine the role of breastfeeding in preventing inflammatory bowel disease and to summarize the evidence gathered about this subject. A meta-analysis was performed on 17 relevant articles that were found by using MEDLINE, EMBASE, the Internet, and articles' references. The publications were fully reviewed and divided, on the basis of their quality, into 3 groups. Studies showed heterogeneous results. The pooled odds ratios of all the 17 reviewed studies, calculated according to the random-effects model, were 0.67 (95% CI: 0.52, 0.86) for Crohn disease and 0.77 (0.61, 0.96) for ulcerative colitis. However, only 4 studies for Crohn disease and 4 for ulcerative colitis were eventually included in the highest quality group. In this group, the pooled odds ratio was 0.45 (0.26, 0.79) for Crohn disease and 0.56 (0.38, 0.81) for ulcerative colitis. The results of this meta-analysis support the hypothesis that breastfeeding is associated with lower risks of Crohn disease and ulcerative colitis. However, because only a few studies were graded to be of high quality, we suggest that further research, conducted with good methodology and large sample sizes, should be carried out to strengthen the validity of these observations.

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Available from: Eyal Klement
Breastfeeding and risk of inflammatory bowel disease: a systematic
review with meta-analysis
1–3
Eyal Klement, Regev V Cohen, Jonathan Boxman, Aviva Joseph, and Shimon Reif
ABSTRACT
Background: It has long been believed that breastfeeding provides
protection against ulcerative colitis and Crohn disease. Studies des-
ignated to test this hypothesis were conducted without reaching
conclusive results.
Objective: The aim of this meta-analysis was to examine the role of
breastfeeding in preventing inflammatory bowel disease and to sum-
marize the evidence gathered about this subject.
Design: A meta-analysis was performed on 17 relevant articles that
were found by using MEDLINE, EMBASE, the Internet, and arti-
cles’ references. The publications were fully reviewed and divided,
on the basis of their quality, into 3 groups.
Results: Studies showed heterogeneous results. The pooled odds
ratios of all the 17 reviewed studies, calculated according to the
random-effects model, were 0.67 (95% CI: 0.52, 0.86) for Crohn
disease and 0.77 (0.61, 0.96) for ulcerative colitis. However, only 4
studies for Crohn disease and 4 for ulcerative colitis were eventually
included in the highest quality group. In this group, the pooled odds
ratio was 0.45 (0.26, 0.79) for Crohn disease and 0.56 (0.38, 0.81) for
ulcerative colitis.
Conclusions: The results of this meta-analysis support the hypoth-
esis that breastfeeding is associated with lower risks of Crohn dis-
ease and ulcerative colitis. However, because only a few studies were
graded to be of high quality, we suggest that further research, con-
ducted with good methodology and large sample sizes, should be
carried out to strengthen the validity of these observations. Am
J Clin Nutr 2004;80:1342–52.
KEY WORDS Crohn disease, ulcerative colitis, breastfeed-
ing, meta-analysis, epidemiology
INTRODUCTION
Despite intensive investigation into the cause and pathogene-
sis of inflammatory bowel disease (IBD), its pathogenic mech-
anism has yet to be elucidated. Several studies indicate that a
genetic basis exists for these diseases and showed a correlation
between disease prevalence and the presence of specific genomic
markers (1, 2). Whatever role genetic loci might play in confer-
ring susceptibility to IBD, studies of identical twins [in which
only 45% of identical twin pairs are concordant for Crohn disease
(CD)] suggest that additional environmental factors are neces-
sary for the development of this disease (3).
To determine which environmental factors contribute to the
development of CD or ulcerative colitis (UC), numerous epide-
miologic studies were performed (4 –7). Factors such as smoking
(8) and use of oral contraceptives (9) were meta-analyzed to
determine their role on the risk of IBD development.
In this meta-analysis, we evaluate another factor, ie, the effect
of breastfeeding, on the later development of UC and CD. The
reasoning is 3-fold. First, breastfeeding protects against many
immune-mediated diseases such as bronchial asthma (10), atopic
dermatitis (11), allergic rhinitis (12), and type 1 diabetes mellitus
(13). This effect is attributed to the immunomodulatory proper-
ties of human milk. From here we hypothesized that if the im-
munomodulatory effect of breastfeeding offers protection
against these diseases, it is plausible to assume similar protection
with regard to UC and CD. Second, the infant is exposed to
human milk while developing an immune system, which seems
to be important in procuring oral tolerance to specific microflora
and food antigens, which can play a role in the pathogenesis of
IBD (14). Third, breast-milk feeding was shown to limit the
development of colitis in mice deficient for interleukin 10. This
finding was explained by the change of intestinal flora of the devel-
oping mice from pathogenic bacteria to nonadherent bacteria as a
result of oligosaccharides found in the milk that stimulate Bifidobac-
terium and Lactobacillus growth (15). A change in proinflammatory
cytokine secretion can also be offered as an explanation (16).
Yet, most of the findings about the beneficial effect of breast-
feeding derive from epidemiologic studies. Indeed, some studies
found breastfeeding to be protective against UC or CD (17–22).
However, most of the studies failed to achieve statistically sig-
nificant results or found no association at all (4, 5, 23–30). Meta-
analyses of observational studies present particular challenges
because of inherent biases and differences in study designs (31).
Thus, this meta-analysis, which is reported here according to the
“proposal for reporting” published previously by Stroup et al
(32), does not presume to provide a precise estimate of the as-
sociation between breastfeeding and IBD but rather attempts to
1
From the Koret School of Veterinary Medicine, the Hebrew University
of Jerusalem, Rehovot, Israel (EK and AJ); the Center for Vaccine Devel-
opment and Evaluation, Israel Defense Forces, Ramat-Gan, Israel (EK, RVC,
and JB); the Pediatric Gastroenterology Unit, Dana Children’s Hospital,
Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel (SR); and the Sackler
Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel (SR).
2
Supported by the Tel-Aviv Sourasky Medical Center.
3
Reprints not available. Address correspondence to E Klement, Koret
School of Veterinary Medicine, The Hebrew University of Jerusalem, Pob
12, Rehovot, Israel. E-mail: klement@agri.huji.ac.il.
Received February 27, 2004.
Accepted for publication June 21, 2004.
1342 Am J Clin Nutr 2004;80:1342–52. Printed in USA. © 2004 American Society for Clinical Nutrition
Page 1
either support or weaken this hypothesis and to summarize the
evidence that was gathered about this subject.
SUBJECTS AND METHODS
Search strategy
A meta-analysis was performed on the basis of a computerized
search of English-written epidemiologic (case-control or cohort)
studies of the association between breastfeeding and UC or CD
listed in the MEDLINE (National Library of Medicine, Be-
thesda, MD) and EMBASE (Elsevier Publishers BV, Amster-
dam) data banks before November 2003. Specifically, a literature
search was performed (by the investigators with the aid of a
professional librarian) by using the index terms ulcerative colitis,
Crohn disease, inflammatory bowel disease, bottle-feeding,
breastfeeding, infant nutrition, perinatal, and milk in various
combinations.
From the abstracts identified in the database search, 14 de-
scribed relevant epidemiologic studies and were selected for full
review (4, 5, 17–26, 28, 29). By reviewing the references of these
articles, 2 additional studies were discovered (27, 30). An Inter-
net search was conducted as well by using the same terms used in
the database search to locate published studies not registered in
MEDLINE or EMBASE. This search recovered one additional
study (33). Thus, a total of 17 studies were fully reviewed in this
meta-analysis.
We selected all studies in which the primary or secondary goal
was to evaluate the association between breastfeeding and UC or
CD as separate entities. These articles were independently re-
viewed by the authors (EK and RVC) by using a standardized
report form. The articles were graded according to predefined
guidelines that will be further detailed. Discrepancies were re-
solved in conferences.
A primary prerequisite for the inclusion of studies in the meta-
analysis was the presence of a control group, which could be
formed by population controls, by hospital inpatients, or by out-
patients who did not suffer from IBD or other chronic diseases
that might be related to lack of breastfeeding. Studies, in which
the control subjects were recruited to the study by the case sub-
jects, with no supervision of the investigators or coinvestigators,
were considered to be of lower quality, because this recruitment
method could inflict a serious selection bias. To further deal with
the problem of selection bias, we categorized the studies according
to the percentage of subjects willing to participate from the total
number of subjects approached by the investigators (response rate);
ie, articles in which the investigators did not detail response rates or
recorded response rates of 80% in either the case or the control
subjects were ranked as having a lower quality.
Studies were categorized according to the age of diagnosis,
from birth to adolescence (0 –18 y) or adults (18 y). To decrease
information bias, studies of adults, which did not specifically
note that the classification of breastfeeding was based on infor-
mation collected from parents or another older relatives of the
participating subjects, were classified as low quality. This clas-
sification was not a requirement in pediatric studies (provided
that data were collected during childhood), because it was as-
sumed that the information was obtained from a parent or an older
relative. No restrictions were imposed on the method in which
this information was obtained (mail, interview, or clinical files).
No restrictions were imposed on the method of diagnosis of CD
and UC. As long as the diagnosis was confirmed by a physician, we
assumed that well-trained specialists diagnosed the cases. Other-
wise, the study was assigned to the low quality group.
Breastfeeding was defined as either exclusive or nonexclusive
breastfeeding for any given duration. Accordingly, no breast-
feeding was defined as nonexclusive or exclusive bottle-feeding
from birth. When odds ratios (ORs) were calculated for both
definitions, we used the OR for “not exclusively breastfed” for
any duration compared with “exclusively bottle-fed from birth”
for the calculation of the pooled estimate. Duration of breast-
feeding was sought and documented.
We did not exclude studies in which the investigators stated
that the correlation between breastfeeding and CD or UC was
insignificant and, therefore, presented neither OR nor crude data.
Instead, the OR was estimated to be 1, and the CI was calculated
by assuming participation of all subjects in the study, and by
arbitrarily assigning them a rate of 20% bottle-feeding. In this
manner we maintained a conservative attitude in which it was
more difficult to spuriously reject the null hypothesis of no re-
lation between breastfeeding and IBD.
To sum up this section, studies were graded for quality levels
as follows. For grade 1 (best quality), case and control subjects
were recruited by the investigators or coinvestigators. Diagnosis
was always confirmed by a physician, and breastfeeding infor-
mation was always confirmed by patients’ mothers or other older
close relative (as previously mentioned, this was not a require-
ment in pediatric studies). Response rate is mentioned in the
article and is 80% for both case and control subjects. Grade 2
was the same as grade 1, except that the response rate is not
mentioned or is 80%. For grade 3 (lowest quality), either
breastfeeding information was not provided by the mother or a
close relative of the patient, diagnosis was not confirmed by a
physician, or control subjects were recruited to the study by the
patients.
Statistical analysis
The pooled OR and its confidence limits were calculated by
using the DerSimonian and Laird method (34), which is based on
the random-effects model. The fixed-effects model– based OR,
calculated as previously described by Greenland (35), is also
presented. In both methods, the weight of each study depends on
the inverse of the variance of log OR, which is estimated by the
95% CI of each study.
Heterogeneity of the studies was calculated with the following
formula:
heterogeneity
2
w
i
[ln(OR
i
) ln(OR)]
2
(1)
The df for the chi-square test was defined as the number of studies
minus one [w
i
represents the weight (calculated by the inverse of
the variance) of each study].
In studies in which both crude and adjusted OR were reported,
we included the adjusted OR in our calculation of the pooled
estimate. If no single adjusted OR was presented, we included the
crude OR. If no OR was presented in a given study, we calculated
it and its 95% CI according to the raw data presented in the article.
Publication bias was investigated by funnel plots and by the
regression asymmetry test for skewed funnel plot introduced by
Egger et al (36). A low P value in this test suggests the possibility
of a publication bias.
BREAST MILK AND IBD 1343
Page 2
Data analysis was performed by using PEPI 4.0 and COM-
PARE2 version 1.25 statistical package (Sagebrush Press, Salt
Lake City) (37). A P value 0.05 was considered to be statis-
tically significant.
RESULTS
Of the 17 studies that were included in the meta-analysis pre-
sented here, 11 investigated both UC and CD, 3 investigated UC
alone, and 3 investigated CD alone. Together a total of 2577
patients with UC and 3551 control subjects and 3190 patients
with CD and 4026 control subjects were studied. The studies are
summarized for UC (Table 1) and for CD (Table 2). Four studies
did not present the exact findings about breastfeeding (4, 23, 27,
30). Instead, they merely claimed that the OR was close to unity.
The OR in those studies was estimated as 1, and the CI was
calculated as described in “Subjects and Methods.” An exception
was made for the study of Gilat et al (4), because this researcher
calculated the OR from the number of discordant pairs of each
case subject and the matched control subject. Thus, the CI for that
study was calculated with half of the control subjects mentioned
in the article (302 pairs of control and case subjects for CD and
197 pairs for UC).
Studies were graded in accordance with the criteria mentioned
in Subjects and Methods (Table 3). Overall, only 4 studies (con-
sisting of 397 patients with UC and 766 control subjects and 583
patients with CD and 876 control subjects) were included in the
highest quality groups for either CD (18, 20, 21, 24) or UC (17,
21, 24, 26). The pooled ORs and 95% CIs (calculated according
to the random-effects model) for these studies were 0.56 (95%
CI: 0.38, 0.81) for UC and 0.45 (95% CI: 0.26, 0.79) for CD. ORs
for the 8 UC studies and the 7 CD studies graded in quality groups
1 and 2 were 0.61 (95% CI: 0.46, 0.83) and 0.55 (95% CI: 0.34,
0.87), respectively. When all studies were included in the pooled
estimate, the random-effects model OR was 0.77 (95% CI: 0.61,
0.96) for UC and 0.67 (95% CI: 0.52, 0.86) for CD (Table 4,
Figures 1 and 2). Thus, the protective effect of breastfeeding
against both diseases remained statistically significant for all
calculated pooled ORs. However, the results for both diseases
appeared to be heterogeneous, primarily after adding the studies
of lower quality (P
heterogeneity
0.001 for CD and P
heterogeneity
҃
0.002 for UC). Heterogeneity was further explored by dividing
the studies according to various characteristics related to popu-
lation differences, exposure definition, and methodologic issues
and by calculating summary estimates of the OR for the associ-
ation of UC and CD with breastfeeding for each group (Table 5).
Exploration of the possibility for publication bias by funnel
plots (Figures 3 and 4) indicated a possible publication bias in
the studies for CD. P value for a skewed funnel plot, calculated
by the regression asymmetry test, was 0.23 for the UC studies and
0.003 for CD studies.
DISCUSSION
The overall pooled OR of this meta-analysis demonstrates that
breastfeeding has a statistically significant protective role
against UC and an even greater role against CD. Because exclu-
sion of studies is subject to criticism as a result of influence of
former beliefs, we did not exclude studies but rather calculated
separate pooled ORs for the best quality studies, for best and
intermediate quality studies, and for all studies. The protective
effect of breastfeeding against both diseases remained statisti-
cally significant for all calculated pooled ORs.
The test for heterogeneity, however, was statistically signifi-
cant for both UC and CD. This finding can be partly explained by
differences in the case subjects’ age (children and adolescents
compared with adults), control subjects characteristics (hospital
based compared with population based), matching variables, and
the exact definition of breastfeeding (Table 5). Heterogeneity of
the studies can also be attributed to the differences in the quality
of the studies, because the results become more heterogeneous
when studies with lower quality are included. These differences
can be due to biased results of these studies. Of special concern
is the study of Thompson et al (28). That study incorporated
hundreds of CD and UC case subjects in its investigation. Thus,
despite methodologic problems, which made it highly prone to
various biases, it had the highest influence on the pooled OR and
the heterogeneity of the studies.
All but 2 studies recovered in this meta-analysis were retro-
spective case-control studies. That type of study constitutes a
drawback because case-control studies are subject to misclassi-
fication as a result of recall bias and to selection bias. It is,
however, difficult to conduct a prospective study that tests the
relation between IBD and breastfeeding, because the lag between
breastfeeding and the development of IBD is substantial. In 2 of
the studies (24, 29), however, data about breastfeeding was col-
lected from medical records and, thus, did not rely on the recall
of mothers. Nevertheless, these data were recorded merely a few
days after labor. The implications of this data collection will be
further discussed later in this article.
Selection bias is potentially present in all of the reviewed
studies, because no study described a comparison between sub-
jects participating in the study and subjects excluded or not
willing to participate. We set a low rank to studies in which the
case subjects were instructed to obtain replies to the control
subject’s questionnaire by themselves, because the process of
selecting and questioning the control subjects by the case sub-
jects without the supervision of the investigators is, in our opin-
ion, highly prone to selection bias. To further minimize the pos-
sibility of selection bias, we calculated a distinct pooled OR for
the studies in which response rate was specified and was 80%.
Another potential source of bias is related to imprecise recall
of breastfeeding. Thus, studies in which information about
breastfeeding was not provided by the mother of the patient or an
older close relative were assigned to the lowest quality group.
Data provided by mothers, theoretically, could also be prone to
recall bias, when one considers the prolonged lag time elapsing
from infancy to development of the disease. However, we tend to
think that this kind of bias was not an important problem in those
studies. Our thought is supported by a study conducted by Launer
et al (38) that demonstrated a high accuracy in the recall of
breastfeeding duration at 18 mo after birth. Although in the
reviewed studies, breastfeeding practices were inquired years
after birth, the information that the mothers were asked to obtain
was simple (breastfeeding, yes or no); hence, we believe it was
accurate. Furthermore, our thoughts are supported by Bergstrand
and Hellers (18), who mentioned in their study that “most living
mothers were remarkably exact in their information regarding
breastfeeding.” Nevertheless, duration of breastfeeding was not
documented in most of the studies. In light of the dose–response
effect found for both CD and UC by Rigas et al (21) and for CD
1344 KLEMENT ET AL
Page 3
TABLE 1
Case-control studies testing the association between breastfeeding and ulcerative colitis
1
Authors, year of
publication, place
Quality
group
Sample size
Matching
(beyond age and
sex) Age (diagnosis) Response rate
Breastfeeding
definition
Duration of
breastfeeding
Crude
OR (95% CI) Adjusted OR (95% CI)Cases Controls
Acheson and
Truelove, 1961
(17), United
Kingdom
(Oxford)
1 101
2
98
2
hospital patients
No Unknown Cases, 87%;
controls, 85%
Exclusive 2 wk 0.34 (0.17, 0.68)
3
Age (at interview) adjusted:
0.38 (0.2, 0.7); residence
region adjusted: 0.4 (0.2,
0.7); rank in family
adjusted: 0.39 (0.21, 0.71);
social class adjusted: 0.35
(0.18, 0.66)
4
Ekbom et al, 1990
(24), Sweden
(Uppsala)
1 164 328 population based
(infant born to the first
mother who was
admitted to the
hospital maternity
ward after the case’s
mother)
Yes; by time of
birth, mother’s
number of
previous
deliveries, and
age
Median age (of
patients with
ulcerative colitis
and Crohn
disease): 25 y
Irrelevant (data
reviewed from
medical records)
Exclusive Unknown
(mean time
of data
availability:
10 d)
0.8 (0.5, 1.4) NA
Koletzko et al, 1991
(26), Canada
(Toronto)
1 93 138 unaffected siblings Yes; inherent in
control selection
Mostly children 92% No exact
definition
No exact
definition
NA 0.59 (0.27, 1.3) adjusted by
conditional logistic
regression for sex and for
having diarrheal disease
during infancy
Rigas et al, 1993
(21), United
States (New
York)
1 39 202 hospital controls
having other
gastrointestinal
problems
No Children Irrelevant (data
reviewed from
medical records)
No exact
definition
No exact
definition
0.5 (0.25, 1.01)
3,5
0.2–0.7 (depends on number
of months of
breast-feeding); adjusted
for sex, age, race,
birthplace, sibship size,
birth order, and maternal
age;
pooled adjusted OR for all
breastfeeding durations:
0.56 (0.3, 1.03)
4
Whorwell et al,
1979 (22),
United Kingdom
(Southampton)
2 51 102 population and
healthy hospital
controls
No Unknown Unknown Exclusive No exact
definition
0.32 (0.14, 0.75)
3
NA
Gilat et al, 1987 (4),
9 countries
(Europe, North
America,
Mediterranean)
2 197 197
6
population and
hospital controls
Yes; by health
center
Mostly children Unknown No exact
definition
No exact
definition
1 (0.61, 1.64)
7
NA
Kono et al, 1994
(23), Japan
2 84 107 hospital controls free
of cancer, peptic ulcer,
and autoimmune and
chronic bowel disease
Yes; by inpatient
status
Children and adults Unknown No exact
definition
No exact
definition
1 (0.49, 2)
7
NA
(Continued)
BREAST MILK AND IBD 1345
Page 4
TABLE 1 (Continued)
Authors, year of
publication, place
Quality
group
Sample size
Matching
(beyond age and
sex) Age (diagnosis) Response rate
Breastfeeding
definition
Duration of
breastfeeding
Crude
OR (95% CI) Adjusted OR (95% CI)Cases Controls
Urashima et al,
1999 (33), Japan
2 133 266 healthy persons or
outpatients (excluding
chronic diseases)
Yes
8
; by block of
birth
Children 48.2% Nonexclusive
breastfeeding
No exact
definition
0.53 (0.31, 0.89) NA
Exclusive
breastfeeding
No exact
definition
0.66 (0.4, 1.1)
Corrao et al, 1998
(19), Italy
3 594 594 inpatients and
outpatients with acute
diseases
No Mostly adults Cases, 95%;
controls, 94%
No exact
definition
No exact
definition
0.69 (0.5, 0.94)
3
0.67 (0.48, 0.91) adjusted
by conditional logistic
regression for sex and for
smoking status and use of
oral contraceptives
Thompson et al,
2000 (29),
United Kingdom
3 27 216 population based
nested in 2 cohorts
Yes
8
; by social
class
Unknown Irrelevant (data
reviewed from
medical
records)
No exact
definition
No exact
definition
2.76 (0.86, 8.81) NA
Persson et al, 1993
(27), Sweden
(Stockholm)
3 145 305 population-based
controls
No Children and adults Cases, 80%;
controls, 78%
No exact
definition
2 mo 1 (0.61, 1.64)
7
NA
Wurzelmann et al,
1994 (30),
United States
(North Carolina)
3 181 141 neighbors of the
same sex, race, and
age of patients
Yes
8
; inherent in
control selection
Mostly adults Cases, 73%;
controls, 80%
No exact
definition
No exact
definition
1 (0.58, 1.73)
7
NA
Klein et al, 1998
(5), Israel (Tel-
Aviv)
3 55 144 population and
hospital outpatient
controls
Yes
8
; by country of
origin and
residential
neighborhood
Children and adults Unknown No exact
definition
1 mo 0.81 (0.39, 1.71)
9
NA
Thompson et al,
1995 (28),
United Kingdom
3 713 713 friends or neighbors
of the same sex, ethnic
origin, and age
Yes; by ethnic
origin
Mostly adults 21% No exact
definition
No exact
definition
1.16 (0.9, 1.5) NA
1
Studies in quality groups 1 and 2 are organized according to year of publication. Studies in quality group 3 are organized according to decreasing quality. OR, odds ratio; NA, not available.
2
Analysis included merely cases and controls for whom history regarding breastfeeding status was confirmed.
3
OR and 95% CI were calculated according to the data presented in the article.
4
For all ORs, ORs and 95% CIs adjusted for the specified variable were calculated by using the Mantel-Haenszel method or the fixed-effects model described by Greenland (35) according to the data presented in the article.
5
Negative association trend between duration of breastfeeding and risk of ulcerative colitis.
6
Although 394 controls were included in the study, only half of them (197) were included in the matched analysis.
7
The exact OR was not mentioned. Because the article indicated that no significant difference was found, we assumed the OR to be 1. The CI was calculated according to the sample size by assuming an exposure rate of 20%
in both groups.
8
Matching was not treated statistically in analysis.
9
The OR and 95% CI were calculated according to the data presented in the article, assuming that all patients and controls provided information regarding breastfeeding.
1346 KLEMENT ET AL
Page 5
TABLE 2
Case-control studies testing the association between breastfeeding and Crohn disease
1
Authors, year of
publication, place
Quality
group
Sample size
Matching
(beyond age
and sex) Age (diagnosis) Response rate
Breastfeeding
definition
Minimal
duration of
breastfeeding
Crude
OR (95% CI) Adjusted OR (95% CI)Cases Controls
Bergstrand and Hellers,
1983 (18), Sweden
(Stockholm)
1 308 308 population based Yes
2
; by area of
birth
Children and adults 93% No exact
definition
1 mo 0.28 (0.14, 0.56)
3,4
NA
Koletzko et al, 1989 (20),
Canada (Toronto)
1 114 180 unaffected
siblings
Yes; inherent in
control
selection
Mostly children 88% No exact
definition
No exact
definition
0.28 (0.11, 0.71) 0.26 (0.11, 0.67) adjusted by
conditional logistic
regression for having
diarrheal disease during
infancy
Ekbom et al, 1990 (24),
Sweden (Uppsala)
1 93 186 population based
(infant born to the
first mother who
was admitted to the
hospital maternity
ward after the
case’s mother)
Yes; by time of
birth,
mother’s
number of
previous
deliveries,
and age
Median age (of
patients with
ulcerative colitis
and Crohn
disease): 25 y
Irrelevant (data
reviewed from
medical
records)
Exclusive Unknown (mean
time of data
availability:
10 d)
1 (0.5, 2.2) NA
Rigas et al, 1993 (21),
United States (New
York)
1 68 202 hospital controls
having other
gastrointestinal
problems
No Children Irrelevant (data
reviewed from
medical
records)
No exact
definition
No exact
definition
0.48 (0.27, 0.85)
3,4
0.1–0.7 (depends on number
of months of
breastfeeding); adjusted
for sex, age, race,
birthplace, sibship size,
birth order, and maternal
age; pooled adjusted OR
for all breastfeeding
durations: 0.58 (0.32,
1.07)
5
Whorwell et al, 1979 (22),
United Kingdom
(Southampton)
2 57 114 population and
healthy hospital
controls
No Unknown Not clear Exclusive
breastfeeding
No exact
definition
1 (0.45, 2.23)
4
NA
Gilat et al, 1987 (4), 9
countries (Europe,
North America,
Mediterranean)
2 302 302
6
hospital controls
Yes; by health
center
Mostly children Unknown No exact
definition
No exact
definition
1 (0.67, 1.49)
7
NA
Urashima et al, 1999 (33),
Japan
2 42 126 healthy persons or
outpatients
(excluding chronic
diseases)
Yes
2
; by block
of birth
Children 44.7% Nonexclusive
breastfeeding
No exact
definition
0.3 (0.13, 0.7) NA
Exclusive
breastfeeding
No exact
definition
0.46 (0.19, 1.1)
Corrao et al, 1998 (19),
Italy
3 225 225 inpatients and
outpatients with
acute diseases
No Mostly adults Cases, 97%;
controls, 94%
No exact
definition
No exact
definition
0.67 (0.4, 1.1)
4
0.53 (0.3, 0.91) adjusted by
conditional logistic
regression for sex and for
smoking status and use of
oral contraceptives
(Continued)
BREAST MILK AND IBD 1347
Page 6
TABLE 2 (Continued)
Authors, year of
publication, place
Quality
group
Sample size
Matching
(beyond age
and sex) Age (diagnosis) Response rate
Breastfeeding
definition
Minimal
duration of
breastfeeding
Crude
OR (95% CI) Adjusted OR (95% CI)Cases Controls
Thompson et al, 2000 (29),
United Kingdom
3 24 186 population based
nested in 2 cohorts
Yes
2
; by social
class
Unknown Irrelevant (data
reviewed from
medical
records)
No exact
definition
No exact
definition
0.4 (0.15, 1.03) NA
Persson et al, 1993 (27),
Sweden (Stockholm)
3 152 305 population-based
controls
No Children and adults Cases, 83%;
controls, 78%
No exact
definition
2 mo 1 (0.61, 1.63)
7
NA
Wurzelmann et al, 1994
(30), United States
(North Carolina)
3 322 262 neighbors of the
same sex, race, and
age of patients
Yes
2
; inherent
in control
selection
Mostly adults Cases, 73%;
controls, 80%
No exact
definition
No exact
definition
1 (0.67, 1.5)
7
NA
Gruber et al, 1996 (25),
United States (New
York)
3 54 90 controls selected
from offspring of
friends, neighbors,
and acquaintances
of mothers of the
cases
Yes
2
; inherent
in control
selection
Children and young
adults (diagnosis
under the age of
22 y)
72% No exact
definition
No exact
definition
0.6 (0.29, 1.3) NA
Klein et al, 1998 (5), Israel
(Tel-Aviv)
3 33 144 population and
hospital outpatient
controls
Yes
2
;by
country of
origin and
residential
neighborhood
Children and adults Unknown No exact
definition
1 mo 0.67 (0.28, 1.6)
8
NA
Thompson et al, 1995 (28),
United Kingdom
3 1396 1396 friends or
neighbors of the
same sex, ethnic
origin, and age
Yes; by
ethnicity
Mostly adults 21% No exact
definition
No exact
definition
1.04 (0.9, 1.25) NA
1
Studies in quality groups 1 and 2 are organized according to year of publication. Studies in quality group 3 are organized according to decreasing quality. OR, odds ratio; NA, not available.
2
Matching was not treated statistically in analysis.
3
Negative association trend between duration of breastfeeding and risk of Crohn disease.
4
The OR and 95% CI were calculated according to the data presented in the article.
5
For all ORs, ORs and 95% CIs adjusted for the specified variable were calculated by using the fixed-effects model described by Greenland (35) according to the data presented in the article.
6
Although 604 controls were included in the study, only half of them (302) were included in the matched analysis.
7
The exact OR was not mentioned. Because the article indicated that no significant difference was found, we assumed the OR to be 1. The CI was calculated according to the sample size by assuming an exposure rate of 20%
in the control group.
8
The OR and 95% CI were calculated according to the data presented in the article, assuming that all patients and controls provided information regarding breastfeeding.
1348 KLEMENT ET AL
Page 7
by Bergstrand and Hellers (18), we think that these missing data
are probably of high importance.
As was mentioned previously in this report, most studies did not
define duration and exclusivity of breastfeeding precisely, and it was
not clear whether exclusive breastfeeding was being compared with
nonexclusive breastfeeding or whether nonexclusive breastfeeding
was being compared with exclusive bottle-feeding. Thus, it cannot
be stated whether the absence of breastfeeding is the risk factor for
IBD or the presence of bottle-feeding. It is also worth noting that this
inadequate definition of breastfeeding duration and exclusivity can
lead to nondifferential misclassification, which might obscure the
protective association between breastfeeding and IBD (39). A good
example for this type of nondifferential misclassification can be
drawn from the study of Ekbom et al (24). That study, although
conducted with almost perfect methodology, defined breastfeeding
according to medical records, which merely documented breast-
feeding status in the first few days after labor. It is possible that a
significant portion of mothers that were assigned in this study as
exclusive breastfeeders moved to partial breastfeeding or totally
gave up breastfeeding a few days later. Thus, the lack of association
found in that study can actually be an underestimation of an existing
association that would have been discovered had breastfeeding sta-
tus been recorded for a longer duration.
Confounding was not treated statistically in most of the stud-
ies. Confounding can potentially bias the results, but the few
studies in which adjusted and crude OR were calculated (17,
19 –21) showed little difference between the adjusted OR that
controls for various confounders (diarrheal disease during in-
fancy, sex, age, race, birthplace, sibship size, birth order, mater-
nal age, smoking, and the use of oral contraceptives) and the
crude OR. We, therefore, believe that the lack of adjustment to
confounders in most of the studies probably did not lead to a
significant bias of the results.
Most of the studies matched case with control subjects for sex
and age. Some studies also matched other variables (region or
TABLE 3
Quality grading of studies
1
Quality group and study UC CD
Recruitment of
controls by
investigators rather
than cases themselves
Breastfeeding
information always
obtained from mother
or older relative
Diagnosis always
confirmed by a
physician
Response rate was
mentioned and
was 80%
1 (highest quality)
Acheson and Truelove, 1961 (17) ѿҀ ѿ ѿ ѿ ѿ
Bergstrand and Hellers, 1983 (18) Ҁѿ ѿ ѿ ѿ ѿ
Koletzko et al, 1989 (20) Ҁѿ ѿ ѿ ѿ ѿ
Ekbom et al, 1990 (24) ѿѿ ѿ ѿ ѿ NA
Koletzko et al, 1991 (26) ѿҀ ѿ ѿ ѿ ѿ
Rigas et al, 1993 (21) ѿѿ ѿ ѿ ѿ ѿ
2 (intermediate quality)
Whorwell et al, 1979 (22) ѿѿ ѿ ѿ ѿ Ҁ
Gilat et al, 1987 (4) ѿѿ ѿ ѿ ѿ Ҁ
Kono et al, 1994 (23) ѿҀ ѿ ѿ ѿ Ҁ
Urashima et al, 1999 (33) ѿѿ ѿ ѿ ѿ Ҁ
3 (lowest quality)
Corrao et al, 1998 (19) ѿѿ ѿ Ҁ ѿ Ҁ
Thompson et al, 2000 (29) ѿѿ ѿ ѿ Ҁ NA
Persson et al, 1993 (27) ѿѿ ѿ Ҁ ѿ Ҁ
Wurzelmann et al, 1994 (30) ѿѿ ѿ Ҁ ѿ Ҁ
Gruber et al, 1996 (25) Ҁѿ Ҁ ѿ ѿ Ҁ
Klein et al, 1998 (5) ѿѿ ѿ Ҁ ѿ Ҁ
Thompson et al, 1995 (28) ѿѿ Ҁ Ҁ ѿ Ҁ
1
See text for grading considerations. Studies in quality groups 1 and 2 are organized according to year of publication. Studies in quality group 3 are
organized according to decreasing quality. UC, ulcerative colitis; CD, Crohn disease; NA, not applicable.
TABLE 4
Pooled estimates for correlation between breastfeeding and risk of ulcerative colitis (UC) and Crohn disease (CD)
1
CD UC
n of
studies
OR (95% CI)
P for
heterogeneity
n of
studies
OR (95% CI)
P for
heterogeneity
Fixed-effects
model
Random-effects
model
Fixed-effects
model
Random-effects
model
Quality group 1 4 0.46 (0.32, 0.65) 0.45 (0.26, 0.79) 0.063 4 0.57 (0.41, 0.79) 0.56 (0.38, 0.81) 0.268
Quality groups 1 and 2 7 0.63 (0.49, 0.80) 0.55 (0.34, 0.87) 0.003 8 0.64 (0.51, 0.80) 0.61 (0.46, 0.83) 0.093
Quality groups 1, 2, and 3 14 0.86 (0.76, 0.96) 0.67 (0.52, 0.86) 0.001 14 0.83 (0.75, 0.95) 0.77 (0.61, 0.96) 0.004
1
OR, odds ratio
BREAST MILK AND IBD 1349
Page 8
country of birth, residential neighborhood), and in some match-
ing was inherent in the control subject selection (neighbors, ac-
quaintances, siblings). However, only in a few of the studies was
matching statistically treated through conditional logistic regression
or McNemar test. The lack of this statistical treatment in most stud-
ies can lead to bias of the OR toward unity (no relation); thus, the
result presented in these studies might lead to underestimation of the
protective association between breastfeeding and IBD (40).
Finally, publication bias, which results from a tendency to
publish only significant data, constitutes a potential problem in
every meta-analysis. The funnel plots of both CD and UC show
that most of the studies have about the same precision. The funnel
plot of the CD studies has an asymmetric appearance. This asym-
metry is supported by the low P value (0.003) result in the test for
skewed funnel plot for CD. In meta-analysis of observational
studies, however, larger sample sizes do not necessarily indicate
a higher validity (36). For example, it can be seen that the dis-
torted shape of the plot is caused primarily by the study of
Thompson et al (28), which, as was previously outlined, has the
FIGURE 1. Association between breastfeeding and ulcerative colitis.
The x axis represents the odds ratio (OR) depicted on a logarithmic scale. ORs
are represented by small white squares, and 95% CIs are represented by lines.
Pooled ORs for group 1, groups 1 and 2, and all studies were calculated by
using the random-effects model whenever possible. Otherwise, calculation
was performed according to the fixed-effects model. Studies in quality
groups 1 (highest) and 2 are organized according to date of publication.
Studies in quality group 3 are organized according to decreasing quality.
FIGURE 2. Association between breastfeeding and Crohn disease. The
x axis represents the odds ratio (OR) depicted on a logarithmic scale. ORs are
represented by small white squares, and 95% CIs are represented by lines.
Pooled ORs for group 1, groups 1 and 2, and all studies were calculated by
using the random-effects model whenever possible. Otherwise, calculation
was performed according to the fixed-effects model. Studies in quality
groups 1 (highest) and 2 are organized according to date of publication.
Studies in quality group 3 are organized according to decreasing quality.
1350 KLEMENT ET AL
Page 9
largest sample size but suffers from some important method-
ologic problems. In addition, most of the studies were performed
for both CD and UC; thus, it is unlikely that publication bias
exists for one but not for the other. Nevertheless, publication bias
cannot be ruled out in this meta-analysis.
In conclusion, our study supports the hypothesis that breast-
feeding provides protection against CD and UC development.
However, it does not presume to provide an exact estimate of the
OR for a certain definition of breastfeeding, but rather to provide
a rough measure of the relation between breastfeeding and the
risk of IBD. Our thought is that, because of a result of nondif-
ferential misclassification, which, as we stated earlier, is inherent
in many of the studies reviewed, the actual effect of breastfeeding
is higher than the one estimated here. Furthermore, most of the
best quality studies showed a significant protective effect. Nev-
ertheless, because the effect found was minor and inconsistent,
FIGURE 3. Funnel plot of precision estimates [calculated by using the
inverse of the SE of ln(odds ratio); ie, the higher the estimate, the more precise
the study] from studies that explored the association between breastfeeding
and ulcerative colitis against their odds ratio. The vertical dashed line is the
summary estimate of the odds ratio for all studies.
FIGURE 4. Funnel plot of precision estimates [calculated by using the
inverse of the SE of ln(odds ratio); ie, the higher the estimate, the more precise
the study] from studies that explored the association between breastfeeding
and Crohn disease against their odds ratio. The vertical dashed line is the
summary estimate of the odds ratio for all studies.
TABLE 5
Summary estimates of the odds ratios (ORs) for the association of ulcerative colitis (UC) and Crohn disease (CD) with breastfeeding according to study
characteristics
1
Study characteristic
UC CD
n
Pooled OR
(95% CI)
P for
heterogeneity n
Pooled OR
(95% CI)
P for
heterogeneity
Quality grade
1 (highest) 4 0.56 (0.38, 0.81) 0.26 4 0.45 (0.26, 0.79) 0.06
2 4 0.67 (0.41, 1.1) 0.06 3 0.71 (0.35, 1.44) 0.04
3 6 0.98 (0.75, 1.28) 0.08 7 0.88 (0.72, 1.08) 0.22
Control characteristics
Hospital based 4 0.6 (0.41, 0.87) 0.15 3 0.71 (0.47, 1.09) 0.11
Population based 6 1.02 (0.81, 1.29) 0.27 8 0.68 (0.48, 0.97) 0.001
Mixed 4 0.64 (0.4, 1.02) 0.09 3 0.59 (0.29, 1.19) 0.12
Adjustment for confounding
2
Yes 4
3
0.59 (0.46, 0.76) 0.55 3 0.48 (0.32, 0.72) 0.32
No 13 0.78 (0.62, 0.99) 0.003 14 0.68 (0.53, 0.88) 0.001
Matching
Yes 9 0.92 (0.73, 1.15) 0.45 10 0.64 (0.46, 0.89) 0.001
No 5 0.57 (0.38, 0.84) 0.05 4 0.7 (0.47, 1.04) 0.14
Breastfeeding definition
Exclusive 4 0.53 (0.34, 0.82) 0.11 3 0.8 (0.5, 1.3) 0.36
Nonexclusive
4
1 0.53 (0.31, 0.89) NA 1 0.46 (0.19, 1.1) NA
Not defined 10 0.91 (0.73, 1.12) 0.11 11 0.66 (0.5, 0.87) 0.001
Participants’ age
Children 4 0.66 (0.46, 0.93) 0.26 4 0.48 (0.25, 0.92) 0.005
Adults 4 0.9 (0.68, 1.2) 0.08 4 0.92 (0.7, 1.2) 0.16
Mixed 6 0.75 (0.44, 1.28) 0.008 6 0.62 (0.4, 0.96) 0.06
1
NA, not applicable.
2
Three studies were included in both categories.
3
For the study by Acheson and Truelove (17), OR adjusted for residence region was included in the pooled analysis.
4
For the study by Urashima et al (33), separate ORs were calculated for exclusive and nonexclusive breastfeeding.
BREAST MILK AND IBD 1351
Page 10
our study should not be regarded as final proof of this hypothesis.
We think that a well-performed, documented prospective study
should be held. Studies of high-risk populations that will specif-
ically address the influence of breastfeeding (as well as its du-
ration) are of particular importance. Because there is a clear
genetic predisposition to IBD, these populations should probably
be composed of families that include persons who already have
IBD [such as the studies conducted by Koletzko et al (20, 26)].
That kind of study will enable the generation of breastfeeding
recommendations to mothers of infants with a history of IBD in
first-degree relatives.
We thank Rina Zakheim for her assistance in the database search for
articles.
EK designed the study, conducted the database search, reviewed the ar-
ticles, analyzed the data, and wrote the manuscript. RVC reviewed the arti-
cles, helped in designing the study and analyzing it, and reviewed the manu-
script; JB reviewed the manuscript; AJ reviewed the manuscript; SR
reviewed the articles and manuscript. None of the authors had any financial
or personal conflicts of interest in any of the subjects discussed in this article.
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    • "Moreover, the influence of early life gut colonization in IBD is further supported by studies reporting association only with CD and higher prevalence specifically in males with antibiotic exposure (Bager et al., 2012; Virta et al., 2012; Li et al., 2014b; Ungaro et al., 2014; Sevelsted et al., 2015). In contrast, breastfeeding is associated with the reduced risk of developing either UC or CD (Klement et al., 2004). Thus, imbalance and microbial dysfunction are observed in childhood IBD pathogenesis and with potential origins lying in early-life colonization patterns. "
    [Show abstract] [Hide abstract] ABSTRACT: Many childhood diseases such as autism spectrum disorders, allergic disease, and obesity are on the increase. Although environmental factors are thought to play a role in this increase. The mechanisms at play are unclear but increasing evidence points to an interaction with the gastrointestinal microbiota as being potentially important. Recently this community of bacteria and perturbation of its colonization in early life has been linked to a number of diseases. Many factors are capable of influencing this colonization and ultimately leading to an altered gut microbiota which is known to affect key systems within the body. The impact of the microbial composition of our gastrointestinal tract on systems outside the gut is also becoming apparent. Here we highlight the factors that are capable of impacting on microbiota colonization in early-life and the developing systems that are affected and finally how this may be involved in the manifestation of childhood diseases. Birth Defects Research (Part C), 2015. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Dec 2015
    • "@BULLET For children, increased risk of impaired postpartum cognitive and visual development (Michaelsen et al. 2003; Vohr et al. 2007; Kramer et al. 2008; Sussmann et al. 2009); child mortality (Chen & Rogan 2004; Department of International Development (DFID) 2006; Edmond et al. 2006); numerous serious diseases, including celiac disease (Chertok 2007), Crohn's disease (Klement et al. 2004), diabetes (Mayer-Davis 2008), diarrhoeal disease and respiratory ailments (Howie et al. 1990; Wilson et al. 1998; Quigley et al. 2007; Morteau et al. 2008; Newburg 2008; Wilson et al. 2008); asthma, ear infection, leukaemia and necrotising enterocolitis (Ip et al. 2007); pathogens in the gastrointestinal tract (Wilson et al. 2008); obesity (Von Kries et al. 2000; Plagemann & Harder 2005; American Institute for Cancer Research (AICR) 2008; American Psychological Association (APA) 2008; Apfelbacher 2008; August et al. 2008; Griffiths et al. 2008; Karaolis-Danckert et al. 2008; Kim & Peterson 2008; Maurage 2008; Hawkins et al. 2009; O'Tierney et al. 2009; Palou & Picó 2009; Simon et al. 2009); sepsis in very low birth weight infants (Hylander et al. 1998); SIDS (McVea et al. 2000; Ip et al. 2007; McKenna et al. 2007; Vennemann et al. 2009) and urinary tract disease (Pisacane et al. 1992; Levy et al. 2008); childhood behavioural or mental health problems (American Public Health Association (APHA) 2008); impaired arsenic metabolism in relevant environments (Fängströn et al. 2008); and, in later life, increased risk of cardiovascular disease (Lawlor et al. 2005; Singhal 2006), higher blood pressure (Martin et al. 2004), higher blood cholesterol concentrations (Owen et al. 2008) and reduced lung function (Tennant et al. 2008; Ogbuanu et al. 2009) @BULLET For mothers, increased risk of haemorrhaging (Sobhy & Mohame 2004) and inadequately spaced pregnancies (Bellagio Consensus 1988; Lawrence 2007); breast cancer (Collaborative Group on Hormonal Factors in Breastfeeding 2002; Martin et al. 2005; AICR 2008; Lord et al. 2008; Phipps et al. 2008; Sotgia et al. 2009; World Cancer Research Fund (WCRF) 2009), uterine cancer (Okamura et al. 2006) and ovarian cancer (Riman et al. 2004); diabetes (Stuebe et al. 2005; Ip et al. 2007); hip fractures and osteoporosis (Turck 2005); gallbladder disease (Liu et al. 2008); higher blood pressure (Jonas et al. 2008); myocardial infarction in middle to late adulthood (Stuebe et al. 2009); postpartum weight retention (Baker et al. 2008); rheumatoid arthritis (Karlson et al. 2004; Pikwer et al. 2009); postpartum relapses in women with multiple sclerosis (LangerGould et al. 2009); and maternally perpetrated child maltreatment, particularly child neglect (Strathearn et al. 2009). Feeding infants and young children appropriately clearly depends on more than breast milk. "
    Full-text · Dataset · Mar 2015 · Immunology Letters
    • "ncidence of inflammatory diseases in childhood and later in life. A meta-analysis of 4 epidemiological studies involving pediatric and adult IBD patients indicated that breast milk exposure reduced the subsequent risk of developing CD (odds ratio, 0.45; 95% confidence interval (0.26–0.79)) and UC (odds ratio 0.56; 95% confidence interval 0.38–0.81) [103] . A subsequent meta-analysis of 7 epidemiological studies of pediatric IBD patients indicated that breast milk exposure had a significant protective effect against development of early-onset IBD (odds ratio, 0.69; 95% confidence interval, 0.51–0.94) [104]. However, both groups of investigators noted the generally poor quality of the epi"
    [Show abstract] [Hide abstract] ABSTRACT: Secretory IgA (SIgA) antibodies in the intestinal tract form the first line of antigen-specific immune defense, preventing access of pathogens as well as commensal microbes to the body proper. SIgA is transported into external secretions by the polymeric immunoglobulin receptor (pIgR). Evidence is reported here that the gut microbiota regulates production of SIgA and pIgR, which act together to regulate the composition and activity of the microbiota. SIgA in the intestinal mucus layer helps to maintain spatial segregation between the microbiota and the epithelial surface without compromising the metabolic activity of the microbes. Products shed by members of the microbial community promote production of SIgA and pIgR by activating pattern recognition receptors on host epithelial and immune cells. Maternal SIgA in breast milk provides protection to newborn mammals until the developing intestinal immune system begins to produce its own SIgA. Disruption of the SIgA-pIgR-microbial triad can increase the risk of infectious, allergic and inflammatory diseases of the intestine.
    Full-text · Article · Dec 2014
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