Functional constipation (FC) is a widespread symptom in infants, accounting for approximately 3% of consultations in an average pediatric practice and up to 25% of referrals to pediatric gastroenterologists (1,2).
Stool frequency depends on the age of the infants. A number of studies revealed a decline in stool frequency from >4 stools per day during the first week of life to 1.7 stools per day at 2 years of age and to 1.2 stools per day at 4 years of age (3,4). Fontana et al (5) showed that in the first 3 years of life, 97% of healthy infants had at least 1 bowel movement on alternate days.
It is known that approximately 16% to 40% of infants with FC develop symptoms during the first 6 months of life (6,7) and that the prevalence of FC in infants in the first year of life is estimated to be 2.9% with a male-to-female ratio of 1.1:1 (8).
Although the pathogenesis of FC remains incompletely understood, the most common cause of FC appears to be an acquired behavior of withholding of stools after the experience of painful defecation. Because of the withholding, the rectal mucosa absorbs water from fecal mass that becomes hard and difficult to be eliminated. This process leads to a vicious circle of stool retention, which is the basis of the persistence of FC in infants (9).
The factors that lead to the painful defecation during the first months of life are not completely known. It has been reported that the FC is less common in the breast-fed infants than formula-fed infants, both in term and in preterm infants (10,11). In a study conducted in children ages >2 years, FC was significantly associated with the female sex, with a low level of maternal education, with the residence in a community with >3000 inhabitants, and with the absence of older siblings (12). Nevertheless, the timing, style, and techniques used for toilet training were not significantly associated with the development of FC in infants (13).
On the contrary, in adults the use of certain medications, such as antacids, diuretics, antidepressants, antiepileptics, and antihistamines, has been associated with an increased risk of chronic constipation (14,15). Moreover, a significant association between acetaminophen, aspirin, nonsteroidal anti-inflammatory drugs, and chronic constipation has been observed in the adult population (16–18).
Although the development of painful defecation during the first year of life is universally recognized as an important trigger for the pathogenesis of FC in the successive years of life, no studies have been conducted in this specific age. This multicenter prospective study aimed to assess the possible risk factors for an alteration of stool habit in infants and the incidence of FC in the first year of life.
The present study was based on a birth cohort of 465 consecutive healthy term newborns, with a weight appropriate to gestational age, enrolled from June 1, 2009 to September 30, 2009, from the pediatric departments of the following: University of Naples “Federico II,” University of Catanzaro “Magna Graecia,” “University of Foggia,” University “La Sapienza” Rome, University of Messina, and University of Padua. The mothers of all of the infants were informed of the study during their hospitalization for the childbirth.
We, then, prospectively followed up the infants up to the first year of life, to evaluate possible risk factors for the development of FC. A total of 402 infants (86.4%) completed the study, whereas the remaining infants (13.6%) were lost during the follow-up.
At the child's age of 3, 6, and 12 months, parents who expressed interest in the study were contacted via telephone by specifically trained physicians to complete 2 questionnaires: one evaluated the presence of FC according to the Rome III criteria (Table 1) (19) and the other screened the possible risk factors for FC.
The bowel habit of infants was assessed by a questionnaire based on the following criteria, related to the month preceding each interview: stool consistency (hard, soft, or firm), stool frequency per week, pain or difficulty in evacuating, mucus in stools, presence of a large fecal mass in the rectum observed with a rectal examination, and retentive posturing during defecation. Infants <6 months of life, who presented with straining and crying before successful passage of soft stools and who did not fulfilled the Rome III criteria for FC, were considered to be affected by infant dyschezia (ID) according to Rome III criteria.
The second questionnaire, as reported in the Appendix (http://links.lww.com/MPG/A273), included the evaluation of the following possible risk factors for FC: breast-feeding duration, intake of vitamins and food supplements, family history of functional gastrointestinal disorders (FGIDs), family history of atopy, weaning and nursery-school age, episodes of fever within 2 weeks before the onset of FC, and the use of drugs (eg, acetaminophen, anti-inflammatory drugs, corticosteroids, antibiotics).
The parents were asked about the modality of feeding of their infants at each interview with the responses being ever breast-feeding, receiving breast-feeding, and receiving mixed breast-feeding and formula-feeding.
If the parents and siblings of the infants have had any medical treatment for FGIDs and/or asthma, allergic rhinitis, food allergy, allergic dermatitis, anaphylactic shock, they were considered to have “family history of FGIDs” and/or “family and/or personal history of atopy,” respectively. Regarding the use of the drug, information on duration of treatment and the symptoms for which infants took these medications were annotated. Moreover, sociodemographic factors screened and included were educational and professional level of the parents, number of siblings, and residence in a community with >3000 citizens.
The infants were excluded if they had symptoms or findings suggestive of illnesses that could cause GI symptoms, a history of major abdominal surgery, acute or chronic physical disease, a developmental disability or diagnosis of organic causes of FC, such as anorectal malformations, changes in the intestinal nerve and muscle structures (Hirschsprung disorder), endocrine and metabolic disorders (hypothyroidism and hypercalcemia), neurological and neuromuscular diseases (central nervous system disorders, spinal cord injuries, and muscular dystrophy), and adverse effects of drugs. At each interview, parents had to answer questions about the presence or the absence of the mentioned conditions, and the eligibility for the study was from time to time decided.
The written informed consent for participation in the present study was obtained from all of the parents of the infants, and the experimental design was approved by the institutional review board of all of the participating centers.
The statistical analysis of the questionnaires was based on the answered questions. All data were stored in a common database and statistically analyzed using the SPSS version 8.0 program (SPSS Inc, Chicago, IL). The variables were screened for their distribution, and the appropriate parametric or nonparametric tests were adopted as required. Cross-tabulations were evaluated by using the Fisher exact test and the χ2 test. The statistical significance was predetermined as P < 0.05. The multivariate conditional logistic regression analysis was used to explore odds associated with the onset of FC. The dependent variable was FC, whereas the effects of all the above-mentioned variables were analyzed by a stepwise procedure.
A total of 465 parents of infants (M/F, 213/252) enrolled at birth completed the questionnaires at 3 and 6 months, whereas 402 infants (M/F, 184/218) were evaluated at 12 months’ follow-up (86.4%). The remaining infants were lost during the follow-up because their parents refused to complete the questionnaires.
In our study population 11.6% of the infants fulfilled the Rome III criteria for FC at 3 months, 13.7% at 6 months, and 10.7% at 12 months after birth. We showed that 23.3% of infants with constipation at 3 months was still constipated at 12 months, whereas 8% of infants without constipation became constipated at 12 months (P = 0.2).
Comparing the presence of FC and sex, we observed that at 3 and at 6 months no statistical differences existed between the infants with constipation and without constipation, whereas at 12 months 29 of 43 (67.5%) infants with constipation were girls compared with 189 of 350 (52.7%) infants without constipation (P = 0.04). In addiction, at 12-month follow-up no significant difference was found for the following variables: standard of living, number of children for each family, mother's education and occupation level, and father's education and occupation level. Tables 2 to 4 report the proportion of infants with FC according to categories of each potential risk factor at 3, 6, and 12 months, respectively.
When we compared the infants without constipation, the presence of familiarity for FGIDs did not result in a significant risk for the development of FC at any follow-up age (P = 0.8, P = 0.6, and P = 0.6 of the 3 follow-ups, respectively). Exclusively, the breast-feeding was significantly related to a normal evacuation pattern at 3 months (P = 0.05), whereas it resulted to have no influence at 6 and 12 months of age (P = 0.12 and P = 0.9, respectively). The results regarding the family history of atopy were reported in Figure 1. We observed a significant association between family history of atopy and FC at 3 and 6 months (P = 0.04 and P = 0.02, respectively), but no association at 12 months (P = 0.8).
Acetaminophen was not a risk factor for the onset of FC at 3 months (P = 0.13), but at 6 months we found a trend toward significance for the use of this drug in the infants with constipation compared with infants without constipation (P = 0.06). At 12 months of life we observed that 79.1% of the infants with constipation had used acetaminophen with respect to 58.2% infants without constipation (P = 0.005). Moreover, any significant association was evaluated by the use of different formulations (syrup, drops, and suppositories) of acetaminophen (P = 0.09). We observed that the main indications for the intake of acetaminophen were fever (75%), cold (30%), dental eruption (15%), and other symptoms such as crying, infant colics, and vaccination (5%). Overall, no statistically significant association was detected for the use of antibiotics, anti-inflammatory drugs, and corticosteroids.
No statistically significant association with FC in infants was observed for intake of vitamins and food supplements, weaning and nursery school age, episodes of fever within 2 weeks before the onset of FC, education and profession level of the parents, number of siblings, and residence in a country with >3000 citizens, at any studied age.
A total of 29 infants <6 months (6%) had ID according to Rome III criteria. The data for these infants were not included in the data on symptoms of FC. Nevertheless, we evaluated whether an association between ID and the onset of FC could exist and we observed that only 3 (6.9%) infants with FC at 12 months have had a diagnosis of ID in the first months of life (P = 0.07).
Overall, after adjustment for all of the analyzed variables, FC in infants was significantly associated with the use of acetaminophen (odds ratio 6.98, 95% confidence interval 0.82–13.50). In the first year of life, none of the other analyzed variables were associated with the onset of FC at 12 months of life.
In this multicenter study we found that breast-feeding is a protective factor for FC in the first 3 months of life and that female sex and the use of acetaminophen are associated with development of constipation in the first year of life.
We observed that breast-feeding has a protective role in the first months of life for the development of FC. Exclusively, breast-feeding resulted in a normal defecation pattern until 3 months of age, whereas it did not affect the bowel habit at 6 and 12 months of age. It is known that breast-fed infants have a significantly higher number of stools per day compared with formula-fed infants (5,20). In addition, it has been reported that the influence of breast-feeding on the bowel habit disappears after the 16th week of life (10). Tunc et al (21) observed a significant difference between breast-fed and formula-fed infants in term of stool consistency and stool frequency in the first 4 months and 6 months of age, respectively. A possible explanation may be researched in the different composition of breast and formula milks. As a matter of fact, Quinlan et al (22) demonstrated that formula milk contains higher levels of lipids and minerals, concluding that calcium fatty acid soaps are positively related to stool hardness.
In the present study, we report that the use of acetaminophen is a potential risk factor for FC in infants at 12 months of life, with a significant trend at 6 months of life. To our knowledge, this is the first multicenter study investigating the relation of FC with drugs commonly used in infants. In 2007, Chang et al (16) reported a significant association between chronic constipation and the use of acetaminophen in adult patients. The exact role of acetaminophen in inducing chronic constipation is not well known. The authors postulated 3 possible mechanisms: an increased intake as a result of the higher frequency of abdominal pain and/or somatic complaints, the use of a formulation with the addition of an opiate, and the possible antiserotoninergic effects of acetaminophen. Serotonin is involved in GI motility, secretion, and sensation. Considering the role of serotonin signaling in the GI tract and the use of serotonin agonists as anticonstipation drugs, it is plausible that an antiserotonergic pathway may be responsible for the association between acetaminophen and constipation. As reported by Chang et al, we excluded the first 2 hypotheses. The main indications for acetaminophen in our infants were fever, cold, and dental eruption, and no formulation with the opiate addition has been used. Moreover, considering the high volume of use of suppositories in children we thought of a possible correlation with this kind of formulation. We, however, did not find any significant association between different formulations of acetaminophen and FC. Therefore, we speculate that the antiserotoninergic action of acetaminophen may be a possible explanation for this association, even if this mechanism remains controversial (23). No significant association between FC and the other analyzed drugs, such as anti-inflammatory drugs, corticosteroids, and antibiotics, was found in our study.
We observed a higher prevalence of FC in girls compared with boys, with a female-to-male ratio of 2:1 at 12 months of age. In the literature, a variance in the prevalence of constipation between the sexes is reported. In particular, some studies found a slightly higher prevalence of constipation in girls compared with boys (24,25), and others reported similar prevalence rates between boys and girls (8). The reasons for female predominance cannot be explained in our population on the basis of the data collected.
Chan et al (26,27) reported that adults with FC showing a familial aggregation had more severe or refractory symptoms. We found that 41% of children with FC had mothers with FC (28). FC, as with the other FGIDs, seems to have a multifactorial etiology. Levy et al (29) found evidence for both a genetic and a social learning contribution to the intergenerational transmission of irritable bowel syndrome (IBS) symptoms. Although heredity may contribute to the tendency of IBS to have a familial aggregation, concordance rates between parents and children compared with those between identical twins indicate that environmental factors such as learning are likely to have an equal or greater influence on the development of IBS (30). In the present study, we did not find any association between FC and familiarity for FGIDs. This finding may be explained by the early age of the studied population. As a matter of fact, in the first year of life, it is plausible that the environmental components do not have such an important role in determining the onset of FC.
The family history of atopy did not result in an independent risk factor for FC, by the multivariate conditional logistic regression analysis, at any studied age. We, however, observed a higher prevalence of family history of atopy in children with constipation compared with children without constipation at 3 and 6 months of life. Regarding the relation between cow's-milk allergy (CMA) and FC, conflicting data have been reported. Iacono et al (31) and Daher et al (32) reported that in young children, FC can be a manifestation of CMA. Conversely, Loening-Baucke (33) found an extremely low prevalence (2%) of food allergy in children <2 years of age with FC (8) and a lack of improvement in FC after a 2-week elimination diet. In an Italian population study, the prevalence of atopy among children with FC (27.3%) was similar to that of the general population (20%) (34). Moreover, Irastorza et al (35) observed that no significant statistical difference was found in terms of atopy or allergic history between children with constipation who responded to cow's-milk–free diet and children with constipation who did not respond. Saps et al (36) showed that even if 44.2% of children with a history of CMA reported GI symptoms, including constipation, the association between constipation and CMA was not significant.
Socioeconomic status and education level seem to be related to the development of FC in both adults and children (12). We did not, however, find any correlation between FC and intake of vitamins and food supplements, weaning and nursery school age, episodes of fever within 2 weeks before the onset of FC and sociodemographic factors, such as the education level of parents, the income level of the family, parents’ occupation, and living in a highly densely populated community. This is probably because of the early age of our study population.
One point of strength of our study is certainly the relevance of the problem. The majority of patients develop constipation during the first year of life and one-third of them is still constipated after puberty. This is an enormous cost to national health systems. Therefore, it is extremely important to recognize the early risk factors, especially in girls, in building a prevention strategy to minimize the development of FC.
This multicenter study examined several potential risk factors for FC and identified an association with the use of acetaminophen and the female sex, while confirming the protective role of breast-feeding. The association with acetaminophen has not been reported in the pediatric population, but this warrants further investigation.
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