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Original Articles: Gastroenterology

Prevalence of Functional Gastrointestinal Disorders in Brazilian Infants Seen in Private Pediatric Practices and Their Associated Factors

de Morais, Mauro Batista*; Toporovski, Mauro Sergio; Tofoli, Marise Helena Cardoso; Barros, Karina Vieira§; Silva, Luciana Rodrigues; Ferreira, Cristina Helena Targa

Author Information
Journal of Pediatric Gastroenterology and Nutrition: July 2022 - Volume 75 - Issue 1 - p 17-23
doi: 10.1097/MPG.0000000000003469

Abstract

What Is Known

  • Functional gastrointestinal disorders (FGIDs) in infants are common worldwide, but their prevalence vary widely.
  • There is little information on the association between FGIDs and history of prematurity, cesarean section, and exclusive breastfeeding.

What Is New

  • Gastrointestinal symptoms are common in infants. This is the first study assessing the prevalence of five FIGDs according to Rome IV criteria in Brazilian infants seen in private pediatric clinics.
  • A significant number of infants with gastrointestinal symptoms did not meet Rome IV criteria.
  • Infant regurgitation, colic, dyschezia, and functional constipation are associated with history of prematurity, but not with cesarean delivery and exclusive breastfeeding.

The first 1000 days from conception are a critical period for the definition of human health at all stages of life (1). During this period, there is significant anatomical growth, functional maturation, and development of gut microbiota in the gastrointestinal tract (2,3). This complex scenario is favorable to the appearance of gastrointestinal symptoms that are part of functional gastrointestinal disorders (FGIDs) in infants (2,3).

Information on the prevalence of FGIDs in infants is still limited and presents results with considerable variability, due to the use of heterogeneous nomenclature and diagnostic criteria (4–11). To date, only two articles (8,11) have used Rome IV criteria (12) to evaluate the prevalence of FGIDs in infants. Gastrointestinal symptoms are also important in the pediatric practice because in addition to the discomfort caused by gastrointestinal symptoms in the infant, there may also be other short- and long-term outcomes that impact both the infants and their families (4,13). There is also an economic impact related to medical care and treatment of FGIDs and their complications (10,13).

In Brazil, there is an alarming rate of cesarean sections (14). The type of delivery and the infant’s mode of feeding have a great influence on the development of gut microbiota (15–17). Prematurely born babies may have a specific pattern of microbiota development and delayed maturation of digestive function (3,18). Imbalance in the gut microbiota development and functional immaturity of the gastrointestinal tract may contribute to the onset of FGIDs (12,19,20); however, there is little information on the association between FGIDs and prematurity, type of delivery, and natural breastfeeding (6,7,9,18,21,22). The recognition of factors associated with FGIDs might be helpful to the development of measures to mitigate the negative effects from gastrointestinal symptoms in infancy.

Thus, the present study was conducted to assess the prevalence of the most frequent functional gastrointestinal disorders in Brazilian infants seen in private pediatric clinics and their relationship with cesarean delivery, history of prematurity, and breastfeeding.

METHODS

Study Design

This is a cross-sectional study that enrolled infants in the first year of life from the five geographic regions of Brazil. Pediatricians previously agreed that the research should be carried out in their private offices. The invitation letter for Pediatricians to collaborate in data collection and the delivery of the material used in the research were carried out by scientific consultants from the company sponsoring the research project. The sponsor’s scientific consultants had no participation in the recruitment and data collection. They also had no contact with parents who voluntarily participated in this study. In private offices in Brazil, appointments are made by the supplementary healthcare system or upon payment for the consultation directly to the physician.

Study Population

As the only inclusion criterion, all infants’ ages up to 12 months who attended routine pediatric appointments were considered. Parents answered the questions before starting the consultation with the pediatrician. The following exclusion criteria were defined: cardiorespiratory, neurological, or genetic diseases; history of abdominal surgery; structural gastrointestinal malformation; suspected or diagnosed cow’s milk allergy and gastroesophageal reflux disease, and other serious illnesses. After signing the Informed Consent Form, parents who agreed to participate in the study completed the study protocol with general information about the infant and the occurrence of gastrointestinal clinical manifestations.

The minimum sample size of 2016 infants was estimated to achieve a 2% margin of error for the 95% confidence intervals, assuming the prevalence of FGIDs to be between 5% and 30% (4–11). For sample size estimation, the EPI-INFO version 6 software (Center for Disease Control and Prevention, Atlanta, USA) was used.

The Ethics Committee of Hospital da Criança Santo Antônio in Porto Alegre, Rio Grande do Sul, Brazil, evaluated and approved the project (number: 95930318.3.0000.5683).

Data Collection Instrument

An expert panel with expertise in Pediatric Gastroenterology, comprised of the authors of this research project, developed the symptom-based questionnaire for data collection relative to infant regurgitation, infant colic, infant dyschezia, functional diarrhea, and functional constipation. Rome IV criteria (12) were considered for the preparation of the study questionnaire in Portuguese, as was done in another study carried out in three European countries (11). After all members of the expert panel agreed with the content of the protocol for data collection, ten mothers of infants assessed the content of the questions and confirmed their understanding. The data collection questionnaire contained 20 questions about gastrointestinal symptoms. The answers allowed the application of Rome IV criteria (12) for infant regurgitation, infant colic, infant dyschezia, functional constipation, and functional diarrhea. Demographic data, type of deliver, history of prematurity and current feeding were also collected (Supplemental Digital Content 1, https://links.lww.com/MPG/C792).

Definition of Functional Gastrointestinal Disorders

The specific age for each FGID was respected, according to Rome IV criteria (12), as follows:

  • infant colic up to 5 months old (crying, fussing, and/or irritability for no apparent reason for at least 3 hours in three or more days of the last week), as recommended for clinical research purposes;
  • infant regurgitation from 21 days to 12 months old (two or more regurgitations per day for >3 weeks, in the absence of clinical manifestations suggestive of gastroesophageal reflux disease);
  • infant dyschezia up to 9 months old (straining or crying before evacuating for 10 minutes or more);
  • functional constipation throughout the first year of life (at least two of the following manifestations: two or less bowel movements per week, history of excessive stool retention, history of painful or hard bowel movement, history of large-diameter stools);
  • functional diarrhea from 6 to 12 months (more than three semi-liquid or liquid bowel movements per day, for a period longer than 4 weeks, with the onset of diarrhea after 6 months of age) (12).

Data Analysis

Data was collected from October 2018 to January 2019. Approximately 10% of the 10,000 pediatricians invited allowed the survey to be carried out in their offices. Overall, three to seven infants were recruited from each private clinic. Information from 5158 infants was entered into a spreadsheet (Excel, Microsoft, Redmond, USA) using the double-entry technique; however, information from 78 (1.5%) infants showing evidence of the diseases listed in the exclusion criteria was discarded. Thus, the information from 5080 infants was analyzed. The prevalence and 95% confidence interval (95% CI) were calculated respecting the age range recommended by Rome IV criteria (12) for each of the five FGIDs studied. The Cochran–Armitage test was used to compare the prevalence trend for each of the FGIDs studied in the quarters of the first year of life.

For each FGID studied and for the concomitant occurrence of two or more FGIDs, bivariable and multivariable logistic regression models were used to evaluate the association with gender, age, type of delivery, history of prematurity, and type of feeding as explanatory variables. The linear assumption between age and each of the response variables in logistic regression was assessed using fractional polynomial method (23), which demonstrated that age could not be included as a linear covariable in the logistic model. As the model cannot have a single odds ratio that describes the association between age and the probability of having each of the FIGDs, age was categorized into tertiles or quartiles in order to facilitate interpretation. Terciles were used for infant colic considering its occurrence in a narrower age range. All explanatory variables were included in the multivariable model, and variables without statistical significance were excluded stepwise to reach a final model with only the significant variables. The results were presented as odds ratio (OR) and 95% CI.

P values <0.05 were considered statistically significant. Sigma Plot 11.2 (Systat Software, San Jose, USA) and Stata/SE 15.1 (Stata-Corp., 2017, College Station, TX: StataCorp LLC) were used for statistical analyses.

RESULTS

Out of the 5080 infants, 2545 (50.1%) were male and 2535 (49.9%) were female. Regarding the regional distribution of the infants in Brazil, 64.3% (n = 3265) of them were studied in the Southeast, 12.8% (n = 654) in the South, 10.6% (n = 538) in the Northeast, 9.8% (n = 496) in the Midwest, and 2.5% (n = 127) in the North.

According to the information available, only 20.4% (1013/4956) of infants were born by vaginal delivery and 10.6% (505/4772) had a history of prematurity. The types of feeding at the time of the study, as reported by the parents (n = 4929), were: 45.9% breast milk; 29.6% mixed breastfeeding (breast milk plus infant formula or whole cow’s milk); 23.3%, infant formula; 1.2%, whole cow’s milk.

Table 1 shows the prevalence of the five FGIDs studied in the corresponding age range. Figure 1 shows the prevalence of FGIDs in the four quarters of the first year of life. Functional diarrhea was not included in Figure 1, as only two infants had this FGID. As age increases, there is a decreasing prevalence of infant regurgitation, infant colic, and infant dyschezia. On the other hand, there is an increased prevalence of functional constipation in the second semester of life compared to the first 6 months.

F1
FIGURE 1.:
Prevalence of Functional Gastrointestinal Disorders (percentage) according to the quarter of the first year of life (P value of the Cocharan–Armitage test).
TABLE 1. - Prevalence of infant regurgitation, infant colic, infant dyschezia, functional constipation, and functional diarrhea in infants seen in private pediatric practice in Brazil
FGID specific age range Number of infants Prevalence N (%) 95% Confidence interval
Infant regurgitation 21 days to 1 y 4560 487 (10.7%) 9.8%, 11.6%
Infant colic Under 5 mo 2162 131 (6.1%) 5.1%, 7.2%
Infant dyschezia Under 9 mo 3895 157 (4.0%) 3.4%, 4.7%
Functional constipation Under 12 mo 4506 341 (7.6%) 6.8%, 8.4%
Functional diarrhea 6–12 mo 2186 2 (0.09%) 0.01%, 0.03%
Number of infants with complete information for the use of Rome IV criteria in the respective age range: infant regurgitation (94.3%; 4560/4834), infant colic (93.8%; 2162/2304); infant dyschezia (97.8%; 3895/3991), functional constipation (88.7%; 4506/5080), and functional diarrhea (96.2%; 2201/2287).FGID = functional gastrointestinal disorder.

Table 2 shows bivariable and multiple logistic regression analyses of the factors associated with each FGID. Infants with incomplete information about the independent variables were not included in the statistical analysis. Functional diarrhea was not included in the evaluation of associated factors due to the small number of infants with this FIGD. Multiple logistic regression analysis showed a statistically significant association between infant regurgitation and age (the younger, the greater the association) and prematurity, but not with gender, cesarean section and type of feeding. Infant colic was associated with age under 102 days and prematurity. Gender and type of feeding were not associated with infant colic. The relationship between cesarean section and infant colic did not reach statistical significance (P = 0.054). Infant dyschezia was not associated with gender, type of delivery, and type of feeding. However, it was associated with age below 130 days and prematurity. Finally, functional constipation was associated with age between 162 and 248 days and prematurity.

TABLE 2. - Bivariable analysis and multiple logistic regression analysis of associated factors (gender, age, type of delivery, history of prematurity, and type of feeding) with functional gastrointestinal disorders (infant regurgitation, infant colic, functional dyschezia, and functional constipation)
Multiple logistic regression analysis
Bivariable analysis Initial model Final model
ORcrude 95% CI P ORadjusted 95% CI P ORadjusted 95% CI P
Infant regurgitation (n = 4091)
 Gender, male 1.03 0.85; 1.25 0.781 1.04 0.85; 1.27 0.689
 Age
  21–98 days 7.15 4.72; 10.85 <0.001 7.00 4.59; 10.67 <0.001 7.13 4.71; 10.82 <0.001
  99–169 days 7.46 4.92; 11.32 <0.001 7.38 4.85; 11.22 <0.001 7.45 4.91; 11.30 <0.001
  170–253 days 3.12 2.00; 4.87 <0.001 3.10 1.99; 4.84 <0.001 3.12 2.00; 4.87 <0.001
  >254 days ref. ref. ref.
 Type of delivery, cesarean section 0.83 0.65; 1.05 0.113 0.86 0.67; 1.09 0.208
 History of prematurity, yes 1.44 1.08; 1.92 0.014 1.43 1.06; 1.93 0.019 1.41 1.05; 1.90 0.022
 Type of feeding, mixed or artificial 0.74 0.61; 0.90 0.003 0.96 0.78; 1.18 0.687
Infant colic (n = 1973)
 Gender, male 0.99 0.69; 1.43 0.959 1.01 0.70; 1.47 0.955
 Age
  <55 days 2.94 1.74; 4.96 <0.001 3.03 1.79; 5.13 <0.001 2.98 1.77; 5.04 <0.001
  56–102 days 2.38 1.39; 4.08 0.002 2.40 1.40; 4.12 0.002 2.36 1.38; 4.04 0.002
  >103 days ref. ref.
 Type of delivery, cesarean section 1.61 0.96; 2.68 0.071 1.66 0.99; 2.79 0.054
 History of prematurity, yes 1.92 1.17; 3.16 0.010 1.95 1.18; 3.23 0.010 1.97 1.19; 3.24 0.008
 Type of feeding, mixed or artificial 1.00 0.69; 1.46 0.985 0.97 0.66; 1.43 0.894
Infant dyschezia (n = 3523)
 Gender, male 1.08 0.76; 1.50 0.692 1.08 0.77; 1.51 0.672
 Age
  <67 days 5.46 2.84; 10.48 <0.001 5.95 3.07; 11.50 <0.001 5.52 2.87; 10.60 <0.001
  68–130 days 4.65 2.40; 8.99 <0.001 4.90 2.52; 9.53 <0.001 4.63 2.39; 8.96 <0.001
  131–189 days 2.06 0.99; 4.28 0.052 2.10 1.01; 4.36 0.047 2.06 0.99; 4.28 0.052
  >190 days ref. ref.
 Type of delivery, cesarean section 1.02 0.67; 1.55 0.936 1.05 0.68; 1.61 0.835
 History of prematurity, yes 1.60 1;00; 2.56 0.049 1.56 0.96; 2.51 0.070 1.64 1.02; 2.64 0.039
 Type of feeding, mixed or artificial 1.05 0.75; 1.48 0.765 1.30 0.92; 1.85 0.142
Functional constipation (n = 4057)
 Gender, male 0.91 0.72; 1.15 0.632 0.91 0.72; 1.15 0.442
 Age
  <90 days ref. ref. ref.
  91–161 days 0.95 0.67; 1.35 0.774 0.95 0.66; 1.35 0.761 0.95 0.66; 1.35 0.765
  162–248 days 1.41 1.01; 1.95 0.042 1.38 0.99; 1.93 0.058 1.40 1.01; 1.94 0.045
  >249 days 1.27 0.91; 1.77 0.166 1.24 0.88; 1.76 0.216 1.27 0.91; 1.77 0.166
 Type of delivery, cesarean section 0.82 0.62; 1.08 0.156 0.80 0.60; 1.06 0.113
 History of prematurity, yes 1.44 1.02; 2.03 0.037 1.41 0.99; 1.99 0.054 1.44 1.02; 2.02 0.039
 Type of feeding, mixed or artificial 1.18 0.93; 1.49 0.179 1.10 0.86; 1.41 0.451
CI = confidence interval; OR = odds ratio; ref. = reference (1.0).

At least one of the four FGIDs was found in 447 (29.7%) out of the 1506 infants aged between 21 and 150 days who were assessed simultaneously for infant regurgitation, infant colic, infant dyschezia, and functional constipation. The number and combinations of FGIDs are shown in the Supplemental Digital Content 2, https://links.lww.com/MPG/C793. Three hundred seventy-seven (84.3%) of the 447 infants showed only one FGID, 59 (13.2%) showed two FGIDs, 8 (1.8%) showed three FGIDs, and 3 (0.7%) infants showed all four FGIDs. The bivariable analysis of factors associated to infants showing two or more FGIDs versus those with one or no FGID showed no relationship with male sex, age, cesarean section, and mixed or artificial feeding (Supplemental Digital Content 3, https://links.lww.com/MPG/C794); however, history of prematurity (OR = 3.06; 95% CI: 1.74, 5.37; P < 0.001) was associated with two or more FGIDs.

Table 3 shows the prevalence of infant colic using the alternative Rome IV criteria for clinical practice purposes. The prevalence (26.1%) was higher than that obtained with the criteria for clinical research purposes (6.1%, Table 1). Regarding the other four FIGDs studied, there was a greater number of infants with related gastrointestinal clinical manifestations in relation to the group of infants who met the Rome IV criteria. The frequency of infants with these clinical manifestations was higher than the prevalence of each of the FGIDs, as shown in Table 1.

TABLE 3. - Gastrointestinal symptoms in infants who did not meet Rome IV criteria for functional gastrointestinal disorders
Infants with gastrointestinal symptoms who do not meet Rome IV criteria
Symptom suggestive of infant colic according to the alternative Rome IV criteria for pediatric practice - 565 (26.1%) of 2162 had at least one episode of crying, fussing, or irritability for no apparent reason in the past week
Infants with regurgitation not meeting Rome IV criteria - 909 (19.9%)of 4560 had two or more regurgitations per day; however, regurgitation did not occur every day during the last 21 days
Symptom suggestive of infant dyschezia not meeting Rome IV criteria - 218 (5.6%) of 3895 strained or cried for a period of 5–10 minutes before evacuating soft stools
Symptom suggestive of functional constipation not meeting Rome IV criteria - 605 (13.4%) of 4506 had pain to evacuate, 60 (1.3%) eliminated hard stools, and 78 (1.7%) had pain to pass hard stools
Symptom suggestive of functional diarrhea not meeting Rome IV criteria - 25 (1.1%) of 2186 had more than three bowel movements per day of semi-liquid stools with pieces of food or liquid stools

DISCUSSION

This cross-sectional study is one of the first studies to assess the most frequent FGIDs in infants using Rome IV criteria. The prevalence of infant colic, infant dyschezia, and infant regurgitation decreases with advancing age in infancy. On the other hand, the prevalence of functional constipation was higher in infants ages 6–12 months. Prematurity was associated with infant regurgitation, infant colic, infant dyschezia, functional constipation, and the concomitant occurrence of two or more FGIDs.

To date, only two studies used the Rome IV criteria to assess the prevalence of FGIDs in infants (8,11). The prevalence of FGIDs in our survey in Brazil was similar to that found in 1698 infants younger than 12 months of age studied in well-baby clinics at routine follow-up in the Netherlands, Belgium, and Italy (11). The other article that used Rome IV criteria evaluated 58 American infants in an online survey and showed higher prevalence of FGIDs (8).

Infant regurgitation was found in 10.7% of infants’ ages between 21 days and 12 months. The prevalence decreased over the first year of life. The reduction in the frequency of infant regurgitation is typically attributed to the functional maturation of the lower esophageal sphincter (2,12). Our results confirmed a higher predisposition for premature infants to have regurgitation. Compared to full-term babies, premature infants are believed to have a higher frequency of lower esophageal sphincter relaxation (18).

According to Rome IV criteria recommended for clinical research, infant colic occurred in 8.4% and 3.2% of infants in the first and second quarters of life, respectively. Among the factors involved in the etiology of infant colic, abnormalities in intestinal microbiota establishment have been highlighted (19,21). Our study found a trend (P = 0.054, Table 2) suggestive of an association between cesarean delivery and infant colic. This finding should be further assessed in future studies, considering that dysbiotic establishment of the intestinal microbiota occurs both in infants born by C-section (14–16) and in those with infant colic (19). Thus, there may be a link between these two variables (17,21). On the other hand, there was an association between prematurity and infant colic (OR = 1.97). This result is consistent with a Danish epidemiological study in which computer-assisted telephone interviews were carried out with 62,761 mothers (21). The interviews performed 6 months after delivery showed that infants born before 32 weeks of gestation had a higher odds ratio compared to those born at 40 weeks of gestation (21).

Infant dyschezia is a consequence of the lack of coordination between the abdominal pressure and the relaxation of the pelvic muscles preceding evacuation attempts (12). Our results showed that infant dyschezia occurred similarly in both genders and was not related to the type of delivery or type of feeding. Our data showed that prematurity was associated with an increased prevalence of dyschezia (OR = 1.64). It might be hypothesized that dyschezia is related to a specific pattern of neuromotor development in premature infants. The prevalence of infant dyschezia in our study was similar to that of the other few articles on the topic (8,11,22). Incoordination disappears spontaneously during normal infant development. No therapeutic procedure is required. Diagnosis of infant dyschezia is important so that parents can be informed about its benign and transitory character. Unnecessary procedures, such as the use of suppositories, should be avoided (12).

Our results showed that the prevalence of constipation was higher in the second semester of life. Functional constipation was not associated with artificial breastfeeding, contrary to what was observed in previous studies (24,25), which showed that natural breastfeeding is associated with a higher number of bowel movements, less consistent stool consistency (24) and lower risk of functional constipation (25). Our results also showed that prematurity was associated with an increased probability of functional constipation, in line with the findings of a Danish cohort (21).

Functional diarrhea was found in only two infants. This result is in line with the literature, which shows that functional diarrhea has a much lower prevalence than the other FGIDs (4,5,7,8,10,11). The limited number of infants with functional diarrhea precluded the analysis of its associated factors.

One of the strengths of our study is the number of infants included in the survey, which exceeded the planned sample size and thus provided greater robustness in the evaluation of the factors associated with the different FGIDs. The sample size also allowed the calculation of the prevalence of each FGID in the respective age ranges, with narrow confidence intervals. The proportion of infants studied in each geographic region approached the distribution of the Brazilian population (42.1% in the Southeast, 27.2% in the Northeast, 14.3% in the South, 8.7% in the North, and 7.7% in the Midwest) (26). The diagnosis of the five FGIDs studied was established based on the answers to direct questions prepared by pediatric gastroenterologists in the Portuguese language spoken in Brazil. The data collection questionnaire was previously tested with a group of mothers in order to confirm its understanding and applicability.

Among the study limitations, it is worth mentioning that the recruitment of infants was performed in pediatric offices of the supplementary healthcare system, which is used mostly by higher socioeconomic classes. This may also be an explanation for the high rate of cesarean sections (79.6%), which are more frequent in the highest socioeconomic classes in Brazil (27). The frequency of premature birth of 10.6% of deliveries is consistent with the rate observed in Brazil (28). A previous Brazilian study (29) and a literature review (20) found no association between infant colic and socioeconomic status; however, further studies should include infants seen in the public healthcare system, which provides medical assistance to the majority of the Brazilian population. An additional limitation of the study was the definition of cow milk protein allergy and gastroesophageal reflux disease based solely on information provided by parents. This method may have reduced the precision in the application of the exclusion criteria. Finally, the cross-sectional design hinders the establishment of a causal relationship with the FGIDs-associated factors.

According to the data presented in Table 3, the rate of infants with infant colic as per the pediatric practice recommendation of Rome IV criteria (26.1%) was higher than the prevalence obtained by the criteria suggested to be used in clinical research studies, also recommended in Rome IV criteria. To the best of our knowledge, this is the first study to apply both Rome IV criteria for infant colic in the same infants group. Also, there were several infants who did not meet Rome IV criteria (12) for the other four FGIDs studied, but had some gastrointestinal clinical manifestations that could be of concern to parents. Some examples are shown in Table 3. These gastrointestinal symptoms not meeting Rome IV criteria may potentially cause parenteral concerns besides discomfort in the infant. Some of them might also be eligible for the same therapeutic used for infants who meet Rome IV criteria. Regarding functional constipation, better prognosis is associated with early diagnosis and treatment (30).

CONCLUSION

In conclusion, FGIDs are common in infants seen in the private pediatric practice in Brazil. A significant number of infants with gastrointestinal symptoms do not meet Rome IV diagnostic criteria for FGIDs. The prevalence of infant colic, infant dyschezia, and infant regurgitation decreased throughout the first year of life, while functional constipation was more prevalent in the second semester of life. Multiple logistic regression analysis showed an association between a history of prematurity and infant regurgitation, infant colic, functional dyschezia, and functional constipation.

Acknowledgments:

The authors acknowledge the Brazilian Pediatricians who contributed and made data collection feasible. Camila Abreu and Danone Nutricia Scientific Consultants for their assistance in the development of the different stages of this project.

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Keywords:

breastfeeding; cesarean section; functional gastrointestinal disorders; prematurity

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