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940 ORIGINAL CONTRIBUTIONS nature publishing group

Infant Nutritional Factors and Functional Constipation


PEDIATRICS

in Childhood: The Generation R Study


J.C. Kiefte-de Jong, MSc1,2, J.C. Escher, MD, PhD3, L.R. Arends, PhD4,5, V.W.V. Jaddoe, MD, PhD1,2,6, A. Hofman, MD, PhD6,
H. Raat, MD, PhD7 and H.A. Moll, MD, PhD2

OBJECTIVES: Food allergy and celiac disease may lead to childhood constipation. Early introduction of food
allergens and gluten in the first year of life has been suggested to have a function in these food
intolerances, but it is unclear whether this also holds true for development of childhood constipa-
tion. The aim of this study was to assess the association between the timing of introduction of food
allergens and gluten early in life and functional constipation in childhood.

METHODS: This study was embedded in the Generation R study, a population-based prospective cohort study
from fetal life until young adulthood. Functional constipation at 24 months of age was defined in
4,651 children according to the Rome II criteria of defecation frequency < 3 times a week or the
presence of mainly hard feces for at least 2 weeks.

RESULTS: At the age of 24 months, 12% of the children had functional constipation. Children with functional
constipation got introduced to gluten more often before or at the age of 6 months than
children without functional constipation (37% and 27%, respectively). After adjustment for birth
weight, gestational age, gender, ethnicity, maternal education, and family history of atopy and
chronic intestinal disorders, functional constipation was significantly associated with early gluten
introduction (odds ratio (OR): 1.35; 95% confidence interval (CI): 1.10–1.65). No association
was found between timing of introduction of cow’s milk, hen’s egg, soy, peanuts, and tree nuts
with functional constipation. A history of cow’s milk allergy in the first year of life was significantly
associated with functional constipation in childhood (OR: 1.57; 95% CI: 1.04 – 2.36).

CONCLUSIONS: These results suggest that early gluten introduction in the first year of life provide a trigger for
functional constipation in a subset of children. In case of functional constipation, there also
might be a role for cow’s milk allergy initiated in the first year of life.
Am J Gastroenterol 2010; 105:940–945; doi:10.1038/ajg.2010.96; published online 2 March 2010

INTRODUCTION (11), and obesity (12) have all been suggested as potential deter-
Functional constipation is a widespread symptom in children. minants of this common clinical problem.
Although the reported prevalence vary widely because of differ- Another determinant of interest is food hypersensitivity.
ent definitions (2–23%) (1–3), it can have a great impact on the Several studies showed that in a subset of children, constipation
child’s quality of life (4). Studies have shown that the frequency may be a symptom of cow’s milk allergy (13–17). Iacono et al.
of irritable bowel syndrome (IBS) in adults is higher in those who (15) showed that in 68% of the cases, improvement was reached
had history of childhood constipation, suggesting that risk factors after dietary elimination of cow’s milk in children with functional
may start early in life (5,6). constipation.
The pathophysiology of childhood constipation seems multi- A food protein that may also have a function within this respect
factorial. Genetic predisposition (7), history of gastroenteritis (8), is gluten that has been started to be consumed in the first year of
inadequate oral intake (9,10), low-birth weight and prematurity the child’s life (18). Recently, a hypothesis has been submitted by

1
Department of the Generation R Study Group, Erasmus Medical Center, Rotterdam, The Netherlands; 2Department of Pediatrics, Erasmus Medical Center,
Rotterdam, The Netherlands; 3Department of Pediatric Gastroenterology, Erasmus Medical Center, Rotterdam, The Netherlands; 4Department of Biostatistics,
Erasmus Medical Center, Rotterdam, The Netherlands; 5Department of Psychology, Erasmus Medical Center, Rotterdam, The Netherlands; 6Department of
Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; 7Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands.
Correspondence: H.A. Moll, MD, PhD, Department of Pediatrics, Erasmus Medical Center, PO Box 2060, Rotterdam 3000 CB, The Netherlands.
E-mail: h.a.moll@erasmusmc.nl
Received 30 November 2009; accepted 8 February 2010

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Infant Nutritional Factors and Functional Constipation in Childhood 941

Verdu et al. (2009), suggesting that gluten might generate gastro- maternal smoking, family history of atopy, and family history of
intestinal symptoms even in the absence of clinical celiac disease any chronic intestinal disorder. Level of maternal education was
(CD), a gluten-induced chronic disease associated with intesti- defined as follows: (i) low: no education, primary school, or < 3

PEDIATRICS
nal inflammation and villous atrophy leading to malabsorption years of secondary school, (ii) midlow: >3 years of secondary school,
(19,20). In addition, several studies suggested that the timing of (iii) midhigh: higher vocational training or bachelor’s degree,
gluten introduction may have a function in the development of and (iv) high: academic education (28). Ethnicity of the child was
CD (21). It is, however, unclear whether gluten introduction in defined as follows: if both parents were born in The Netherlands,
the first year of life has a function in functional gastrointestinal the ethnicity was defined as Dutch, if one of the parents was
symptoms such as functional constipation. born in another country than The Netherlands, that country
In case of food allergy, studies have also addressed the possibility counted; if parents were born in the different countries other
to reduce any sensitization to food allergens by delaying the intro- than The Netherlands, the country of mothers counted (29).
duction of the main allergens as cow’s milk, egg, peanuts, nuts, and From obstetric records assessed in mid-wife practices and
soy early in life (22,23). However, the association between allergen hospital registries data on gender, birth weight, gestational age,
introduction and functional constipation in childhood is unclear. and birth outcomes were available (25).
In this epidemiological study, we aim to assess the association Weight and height at the age of 24 months were available from
between the timing of introduction of food allergens and gluten in the child health centers. Body mass index was then calculated
the first year of life and the prevalence of functional constipation and being overweighed was defined according to age- and gender-
in children aged 24 months. dependent body mass index thresholds for young children from
Cole et al. (2000) (30).

METHODS Introduction of food allergens and gluten in the first year of life
Participants and study design At the child’s age of 6 and 12 months, parents were asked at what
This study was embedded in the Generation R study, a popula- age they had introduced the following products in the infant’s diet
tion-based prospective cohort study from fetal life until young for the first time: milk, yoghurt, porridge, egg, bread or biscuits,
adulthood and has been described in detail earlier (24,25). In peanuts, nuts, and soy products. The reported introduction of these
total, 7,893 mothers with a delivery date between April 2002 and food products were cross-checked with a short food-frequency
January 2006 gave consent for follow-up. The study was approved questionnaire filled in at the children’s age of 6 and 12 months
by the medical ethical review board of the Erasmus Medical consisting of food products frequently consumed according to a
Center, Rotterdam, The Netherlands. Dutch food consumption survey in infants (31). For example, if
the parent indicated at the age of 12 months that they had never
Functional constipation introduced peanuts in their infant’s diet but at the infant’s age of
At the age of 24 months, stool pattern of the child was assessed 6 months the parent filled in that the infant consumed peanut
by using a questionnaire (n = 5,500; response: 70%). Accordingly, butter more than once, then the introduction of this allergen was
functional constipation was defined in this study if at least one of considered to be before or equal to 6 months of age. In case of gluten
the following symptoms of ROME II (26) was reported: (i) defeca- introduction, it was additionally cross-checked with the consump-
tion frequency < 3 times a week for at least 2 weeks or (ii) predom- tion of bread and biscuits but also with the type of porridge (based
inantly hard feces for the majority of stools for at least 2 weeks. on wheat or oats instead of rice), which was consumed at the age of
To avoid the influence of metabolic disorders and clustering, 6 and 12 months. In addition, if the parent indicated that porridge
children were excluded in the analyses in case of the following: was introduced in the infant’s diet before the age of 6 months but at
(i) twinborn (n = 238), (ii) siblings within the Generation R cohort the age of 6 months porridge was only based on rice, this product
(n = 343), (iii) presence of a congenital heart condition (n = 47), was considered as not gluten containing and vice versa.
(iv) anemia in the past year (n = 58), or (v) growth retardation Furthermore, in case of the introduction of cow’s milk and
defined as height < − 2 s.d. based on the Netherlands growth soy, the timing of introduction was also cross-checked with
curves of 12–24 months children (n = 163) (27). the type of bottle feeding used at the age of 6 and 12 months
(soy based or whether based on fully hydrolyzed whey protein).
Covariates Data on breast-feeding was not included in the introduction of
At the child’s age of 6 and 12 months, mothers filled in a ques- cow’s milk but analyzed separately as described below.
tionnaire including topics regarding the child’s general health
(i.e., medication use, comorbidity) and the consumption of food Breast-feeding
products, and breast-feeding. Breast-feeding duration was assessed according to five variables:
The presence of cow’s milk allergy was obtained by question- ever breast-feeding, cessation of breast-feeding, and receiving any
naires at the age of 6 and 12, where parents were asked whether breast-feeding at the age of 2, 6, and 12 months.
their child had doctor-attended cow’s milk allergy. Data on ever breastfeeding were collected from delivery reports
Prenatal questionnaires completed by the mother and father and data on breastfeeding cessation or continuation were derived
included information on ethnicity, mother’s educational level and from postnatal questionnaires at 2, 6, and 12 months.

© 2010 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY


942 Kiefte-de Jong et al.

Subsequently, breast-feeding was categorized into six groups:


Table 1. Maternal and child characteristics and functional
(i) never breast-feeding, (ii) partial breast-feeding with duration
constipation (N = 4,651)
of < 4 months and not thereafter, (iii) partial breast-feeding until 6
PEDIATRICS

months of age, (iv) exclusive breast-feeding until 4 months of age No Functional


and not thereafter, (v) exclusive breast-feeding < 4 months, par- constipation constipation
(N = 4,080) (N = 571) P value
tial thereafter, and (vi) exclusive breast-feeding until 6 months of
age. An approximation of exclusive breast-feeding was performed Mother
according to whether the child received breast-feeding without any Educational level of mother, N (%) < 0.01
other bottle feeding, milk, or solids according to the short food Low 620 (15%) 154 (27%)
frequency questionnaire described previously in this section. Par-
Midlow 1,170 (29%) 195 (34%)
tial breast-feeding indicates infants receiving breast-feeding, bottle
feeding, and/or solids in this period. After the age of 6 months, all Midhigh 1,030 (25%) 118 (21%)

infants received complementary feeding. High 1,259 (31%) 104 (18%)


Maternal smoking, N (%) 983 (24%) 171 (30%) < 0.01
Statistical methods Child
First, univariate analyses were performed by using χ2 tests for
Male, N (%) 2,093 (51%) 240 (42%) < 0.01
categorical variables and the Student t-test for continuous vari-
ables (normally distributed). Second, logistic regression analysis Ethnicity, N (%) < 0.01
was performed with functional constipation as dependent vari- Dutch/other Western 3,100 (76%) 321 (56%)
able. Introduction of food allergens and breast-feeding in the first Non-Western 980 (24%) 250 (44%)
year of life were analyzed separately as independent variables and
Birth weight mean (s.d.) 3,479 (535) 3,382 (572) < 0.01
adjusted for major confounders. The selection of potential con-
founders in the multivariate model was carried out by the altera- Gestational age at 40.0 (1.6) 39.7 (1.9) 0.01
delivery (mean; s.d.)
tion in odds ratios (ORs). In case of ≥10% alteration in ORs, the
potential confounder was kept in the multivariate model. Statis-
tical interaction by a history of cow’s milk allergy and/or being
overweight was evaluated by adding the product term of the cov- In children with at least 2 weeks of constipation-related symp-
ariate and subgroup (covariate × subgroup) as an independent toms at the age of 24 months, 22% had ever used laxatives in the
variable to the model. past year compared with 1% children with no constipation or
Out of 4,919 parents who completed the questionnaire at 24 symptoms for a shorter duration than 2 weeks (P < 0.01).
months, 4,651 children were available with data on functional
constipation after exclusion and were defined as the population Introduction of food allergens and gluten
for analysis. As complete data on covariates at 6, 12, and 24 months Early introduction of soy and nuts in the infant’s diet were sig-
of age were available for only 3,009 children, there were some nificantly associated with functional constipation, but this was
missing data for covariates (0.5–25%). For that reason, covariates mainly explained by confounders as gender, mother’s educational
were multiple imputed (n = 5 imputations) based on the correla- level, ethnicity, birth weight, gestational age, maternal smoking,
tion between the variable with missing values with other patient family history of atopy, and family history of intestinal disorders
characteristics (32). Data were imputed according to the Markov (Table 2).
Chain Monte Carlo method (assuming no monotone missing The timing of food allergens such as peanuts, cow’s milk, and
pattern) and the imputations were repeated for five times to hen’s egg in the first year of life was not significantly associated
obtain the five copies of the filled-in data set. Data were analyzed with functional constipation (Table 2).
in each data set separately to obtain desired parameter estimates Introduction of gluten ≤6 months was reported in 37% and 27%
and standard errors. Subsequently, the results of the five imputed of the children with and without functional constipation, respec-
analyses were pooled and reported in this paper as ORs and 95% tively. Children who consumed gluten before the age of 6 months
confidence interval (95% CI). A P value < 0.05 was considered as had a significantly higher prevalence of functional constipation
statistically significant. at the age of 24 months that remained statistically significant in
The statistical analyses were carried out by using SPSS 17.0 for the multivariate model (Table 2). The result did not differ whether
Windows (SPSS, Chicago, IL). the child had a history of cow’s milk allergy in the first year of life
(P > 0.25 for statistical interaction) or was overweight (P > 0.50 for
statistical interaction).
RESULTS
Study population Breast-feeding
Maternal and child characteristics of the study population are Whether mothers had ever breast-fed their child was not signifi-
presented in Table 1. Out of 4,651 children, 12% had symptoms cantly associated with functional constipation in childhood com-
of functional constipation at the age of 24 months. pared with children who were never breast-fed (OR: 0.91; 95% CI:

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Infant Nutritional Factors and Functional Constipation in Childhood 943

Table 2. Associations between the introduction of food allergens Table 3. Associations between breast-feeding and functional
and gluten and functional constipation (N = 4,651) constipation (N = 4,651)

PEDIATRICS
Multivariate Univariate Multivariate
Univariate model modela Duration of model modela
N (%) OR (95% CI) OR (95% CI) breast-feeding N (%) OR (95% CI) OR (95% CI)

Introduction 3,264 (70%) 1.20 (0.95–1.51) 1.09 (0.86 – 1.39) Never 420 (9%) Reference Reference
of cow’s milk
≤6 monthsb Partial breast-feed- 2,181 (47%) 0.95 (0.69 – 1.32) 0.91 (0.66 – 1.25)
ing until 4 months,
Introduction of 1,345 (29%) 1.54c (1.26 – 1.89) 1.35c (1.10 – 1.65) not thereafter
gluten ≤6 months
Exclusive breast- 455 (10%) 0.82 (0.51 – 1.31) 0.83 (0.50 – 1.36)
Introduction of 926 (20%) 1.28c (1.03 – 1.60) 1.13 (0.90 – 1.41) feeding until
soy ≤6 months 4 months, not
thereafter
Introduction 373 (8%) 1.29 (0.82 – 2.02) 1.01 (0.65 – 1.55)
of peanuts Exclusive breast- 798 (17%) 0.73 (0.50 – 1.07) 0.74 (0.51 – 1.07)
≤6 months feeding until
4 months,
Introduction 288 (6%) 1.49c (1.01 – 2.19) 1.20 (0.83 – 1.74) partial thereafter
of tree nuts
≤6 months Partial breast-feed- 735 (16%) 0.93 (0.65 – 1.33) 0.80 (0.55 – 1.16)
ing until 6 months
Introduction 550 (12%) 1.26 (0.97 – 1.65) 1.04 (0.79 – 1.38)
of hen’s egg Exclusive breast- 62 (1%) 0.63 (0.21 – 1.85) 0.63 (0.19 – 2.02)
≤6 months feeding until
6 months
CI, confidence interval; OR, odds ratio.
a
Adjusted for gender, mother’s educational level, ethnicity, birth weight, CI, confidence interval; OR, odds ratio.
a
gestational age, maternal smoking, family history of atopy, and family history Adjusted for gender, mother’s educational level, ethnicity, birth weight,
of intestinal disorders. bExcluding breast-feeding, including bottle feeding gestational age, maternal smoking, family history of atopy, and family history of
containing casein and whey proteins. cP < 0.05. intestinal disorders.
ORs are compared with introduction > 6 months of age.

0.64–1.30 after adjustment for gender, birth weight, gestational constipation. No significant association was found between early
age, mothers educational level, ethnicity, maternal smoking, introduction of food allergens, breast-feeding, and functional con-
family history of atopy, and family history of intestinal disorders). stipation independently of gender, social economic background,
The ORs for functional constipation slightly decreased as the ethnicity, birth weight, gestational age, maternal smoking, family
duration of breast-feeding was longer, but this did not reach statis- history of atopy, or intestinal disorders. The results were also not
tical significance (Table 3). The results did not differ whether the different within strata of a history of cow’s milk allergy or being
child had a history of cow’s milk allergy in the first year of life overweight.
(P > 0.10 for statistical interaction) or was overweight (P > 0.30 To our knowledge, this is the first study that describes the asso-
for statistical interaction). ciation between early nutritional factors and functional constipa-
tion in childhood in a large cohort of healthy children.
Parental report of cow’s milk allergy in first year of life The association between early gluten introduction and func-
Compared with children without functional constipation, a history tional constipation may be explained in several ways. First, early
of cow’s milk allergy was more frequently found in children with gluten introduction might reflect early complementary feeding
functional constipation at the age of 24 months (6% and 9%, respec- in general, as gluten-containing cereals are frequently consumed
tively). Logistic regression analyses revealed that a history of cow’s on a daily basis in young children in the Netherlands (33). Early
milk allergy in the first year of life was significantly associated with complementary feeding may alter the intestinal flora (34). In addi-
functional constipation in childhood (OR: 1.48; 95% CI: 1.03–2.11), tion, Amarri et al. (35) showed that in healthy breast-fed infants,
which remained statistically significant after adjustment for major changes in intestinal microbiota occurred for some intestinal
confounders as gender, mother’s educational level, ethnicity, birth bacteria after introduction of solid foods. It is acknowledged that
weight, gestational age, maternal smoking, family history of atopy, and there is little evidence that altered gut flora may contribute to
family history of intestinal disorders (OR: 1.57; 95% CI: 1.04–2.36). functional constipation in adults, but studies on the gut flora in
young children with functional constipation are inconsistent
with respect to interventions implying to influence the intestinal
DISCUSSION flora (i.e., probiotica) (36,37).
This study shows that early introduction of gluten and a history Second, several studies imply a relationship between early gluten
of cow’s milk allergy was significantly associated with functional introduction and CD (38–40). CD may present with symptoms of

© 2010 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY


944 Kiefte-de Jong et al.

constipation. Ford et al. (20) showed that the prevalence of CD gluten introduction in the first year of life and thus the definition
is higher in subjects with IBS compared with subjects with no of early introduction of gluten should be interpreted with caution
gastrointestinal symptoms. Early gluten introduction has been and needs further study.
PEDIATRICS

proposed to be a risk factor for CD in Swedish epidemiological Furthermore, to define our outcome, we used criteria from
studies (39). Particularly in the first months of life, the infant’s intes- ROME II (26). We were not able to fully specify our outcome
tine is still developing (34). Introduction of gluten during these according to the most recent evidence-based ROME III crite-
months may disrupt gut homeostasis, which may establish glu- ria (48). Although the prevalence of functional constipation in
ten sensitivity or autoimmunity associated with CD in vulnerable our study is comparable with other studies in the general popu-
subjects. Nevertheless, the prevalence of 0.5–1% of clinical CD lation or school samples (2), our results preclude conclusions
in The Netherlands (41), leaves a scientific challenge with respect on allergen introduction in subsets of more severe functional
to our study results. In addition, Verdu et al. (2009) recently constipation.
proposed that gastrointestinal symptoms might be a feature of Finally, we did not have data on psychological factors and
gluten sensitivity but not necessarily clinical CD. The authors on lifestyle in this study population. As this study is of epide-
proposed that even in the absence of CD, gluten may induce symp- miological design, residual confounding by lifestyle and psy-
toms comparable as in functional bowel disorders, which may chological aspects could remain thereby not permitting any
shed some light on our study results. Studies showed that, even in final conclusions with respect to the causality of the described
the absence of classic mucosal injury as seen in CD, improvement associations.
of gastrointestinal symptoms could be reached after a gluten-free In conclusion, this study addresses the possibility that early
diet (19). gluten introduction in the first year of life provide a trigger that
According to the hypothesis of Verdu et al. (19), there might be may explain a part of the spectrum influencing functional con-
some ground that gluten could be responsible for constipation. stipation in childhood. The results do not support a role for the
However, as we only found a 10% difference in early gluten intro- time of introduction of cow’s milk, soy, hen’s egg, peanuts, and
duction between children with and without functional constipa- tree nuts in the development of functional constipation in child-
tion and a gluten-free diet as therapy in constipated patients with hood. The study also described the potential influence of cow’s
no villous atrophy is also controversial; the influence of gluten in milk allergy commenced in the first year of life and the develop-
functional bowel disorders needs definitely further elucidation in ment of functional constipation in childhood. Further clinical
future studies. studies should clarify whether more attention should be paid
It is remarkable that our study shows that parental report to gluten consumption in the first year of life in a subset of
of doctor-attended cow’s milk allergy in the first year of life is children and if constipated children may have prolonged cow’s
still strongly associated with constipation in childhood. Although milk allergy.
several studies suggested that cow’s milk allergy could be a cause
of functional constipation (3,17,42,43), cow’s milk allergy usually ACKNOWLEDGMENTS
resolves within the first few years of life, with already two third The Generation R Study is conducted by the Erasmus Medical
of patients becoming tolerant by the age of 2 years (44,45). In our Center in close collaboration with the School of Law and Faculty of
study, it could be the case that in a proportion of children, cows Social Sciences of the Erasmus University Rotterdam, the Municipal
milk allergy remains but that cow’s milk is not fully eliminated in Health Service–Rotterdam Metropolitan Area, the Rotterdam
the child’s diet, as the diet becomes more diverse after the age of Homecare Foundation, and the Stichting Trombosedienst and
1 year (33,46) that makes symptoms of cow’s milk allergy persist Artsenlaboratorium Rijnmond. We acknowledge the contributions
in childhood. Also, there could be a shift in features of cow’s of children and parents, general practitioners, hospitals and
milk allergy over time with different clinical manifestations later midwives in Rotterdam.
in life compared with symptoms at commencement (16) through
which the allergy seems to pass undeservedly. However, to CONFLICT OF INTEREST
appreciate these results, some limitations of the study have to be Guarantor of the article: H.A. Moll, MD, PhD.
discussed. Specific author contributions: Involvement in the design, planning,
We did not have other evidence of cow’s milk allergy in the first and conduct of the study, and data collection: H.A. Moll, H. Raat,
year than the parental report if the child had doctor-attended cow’s V.W.V. Jaddoe, A. Hofman, J.C. Kiefte-de Jong; statistical analyses
milk allergy. It is known that self-report of food allergy overesti- and interpretation of data: J.C. Kiefte-de Jong, H.A. Moll; statistical
mates the true prevalence of food allergy (47). If these children assistance: L.R. Arends; drafting the final manuscript: J.C. Kiefte-de
were more likely to have persistent constipation at 24 months then Jong, H.A. Moll, J.C. Escher. All authors critically reviewed the
this information bias may have led to overestimation of our study manuscript.
results. Financial support: This phase of the Generation R Study was
From previous epidemiological studies in Sweden (40), we supported by the Erasmus Medical Center, the Erasmus University
have learned that particularly very early gluten introduction (e.g., Rotterdam, the Netherlands Organization for Health Research and
before the age of 4 months) might be a risk factor for CD. Unfor- Development (Zon Mw), and Europe Container terminals B.V.
tunately, our data did not allow assessing any effect of very early Potential competing interests: None.

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Infant Nutritional Factors and Functional Constipation in Childhood 945

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