What Is Known/What Is New
What Is Known
- According to biopsychosocial model, early life events are associated with the development of functional gastrointestinal disorders.
- Studies found an association between Cesarean section and prematurity with irritable bowel syndrome in adults but the data in pediatrics are scarce.
- Early alterations in gut microbiota are common amongst infants born via Cesarean section and premature birth. It is unknown if these alterations persist into childhood.
What Is New
- Delivery via Caesarean section is not associated with an increased prevalence of functional gastrointestinal disorders in children.
- There is a possible increased prevalence of functional nausea in children, amongst preterm infants born between 28 and 32 weeks.
Functional gastrointestinal disorders (FGIDs) are common in childhood. Although the pathogenesis of FGIDs remains unknown, researchers acknowledge that the etiology of FGIDs is multifactorial. There are emerging data on the role of dysbiosis in the pathophysiology of FGIDs. The intestinal microbiota differs between patients with irritable bowel syndrome (IBS) and healthy controls (1). According to the biopsychosocial model, early life events are associated with the development of FGIDs (2). Two of the earliest events that could influence the development of FGIDs are method of delivery and gestational age at time of delivery. Both have been associated with alterations in the gut microbiome (3,4).
Microbiota begins to colonize the newborn gastrointestinal tract shortly after birth (5). Infants born via Cesarean delivery and infants born prematurely are often exposed to threats to intestinal homeostasis (6). Birth-related psychosocial stressors, antibiotics, dysregulation of the gut-brain axis, environmental factors, and inflammation can affect the initial colonization of the gut microbiota (7). Considering that much of this ecosystem remains intact throughout preschool age and adulthood (8), early life events may play a critical role in influencing host-microbiota interactions throughout life. It is, however, unclear if these early changes in microbiome could predispose one to develop FGIDs including IBS later in childhood.
Studies of the mode of delivery and prematurity and their relation to the development of FGIDs are scarce, contradictory, and mostly focused in adults with IBS (9,10). We have conducted a large observational study to assess whether there is an association between mode of delivery, length of gestation, and prevalence of FGIDs in school-aged children. We hypothesized that delivery via Cesarean section and prematurity would be associated with an increased prevalence of FGIDs in children.
This cross-sectional observational study was conducted from February 28 to September 20, 2018 in 1 large city and 2 medium-size geographically dispersed cities of Colombia (Cali 2,471,474, Tuluá 219,138 Palmira 310,608 inhabitants), the second most populated country in South America. To better confer racial, ethnic, and socioeconomic diversity, multiple public schools (2 in Cali, 1 in Tuluá, and 1 in Palmira) were selected for participation.
Study information was sent to the families of all school children. Parents completed informed consent and responded to demographic and past medical history questions including mode of delivery and length of gestation. Similar to our previous studies, participating children completed validated questionnaires to diagnose FGIDs per the Rome IV criteria (Spanish version of the Questionnaire of Pediatric Gastrointestinal Symptoms Rome IV). Our study excluded children with organic intestinal abnormalities including history of abdominal surgical intervention or history of gastrostomy tube, metabolic diseases, and neurologic abnormalities. To analyze the effect of prematurity on FGIDs, only subjects born at <36 weeks of gestation were studied and term data were used for comparison. The study was approved by the principal of each school and the Institutional Review Board and Human Subjects Committee of Universidad del Valle of Cali, Colombia.
Prevalence data were extrapolated for analysis. We used bivariate analysis for 2 paired data sets and multivariate analysis to assess the relationship between >2 variables. We compared the data of children with and without FGIDs using the 2-sided Student t test for continuous variables and χ2 and Fisher exact tests for categorical variables when appropriate (Stata 10 software; StataCorp, College Station, TX). Calculation of odds ratio with 95% confidence interval was performed between the variables of interest (age group and sex) and the effect variable (presence or absence of FGID). Statistical significance was set at P < 0.05.
A total of 1980 surveys were mailed to the families of school-aged children. Out of those, 1647 (83.2%) surveys were returned. One hundred fifty responses were excluded due to medical comorbidities (Fig. 1). In total, 1497 children/adolescents (535 preadolescents 10–12 years, and 962 adolescents 13–18 years) were included the study, mean age 13.4 ± 2.1 years (71% girls). The strong predominance of girls occurred because an all-girls school was included (Tuluá) (n = 663). Geographic regional distribution of participants was: Cali (n = 450), Tuluá (n = 701), and Palmira (n = 346) (Table 1).
Rome IV criteria for at least 1 FGID were met by 22.7% of all children. Defecation disorders were the most common group of FGIDs (13%), followed by abdominal pain disorders (5.8%) and disorders of nausea/vomiting (3.9%) (Table 2).
Mode of Delivery
Birth by Caesarean section occurred in 30.6% of children, whereas 69.4% were born via vaginal delivery. There was no significant difference in the prevalence of FGIDs between those born via Caesarean section and those born by vaginal delivery (Table 3).
Length of Gestation
Eighty-five percent were born at term (37–41 weeks’ gestation), 13.4% preterm (<37 weeks’ gestation), and 1.7% post-term (>42 weeks’ gestation). In bivariate analysis, there was a higher prevalence of FGIDs among those born between 28 and 32 weeks (P = 0.03) compared with other lengths of gestation. See supplemental Table 1 (Supplemental Digital Content, https://links.lww.com/MPG/B738). Among all FGIDs, the only diagnosis that was more prevalent in this age group was functional nausea (P = 0.02). The significance of this finding was lost when data were analyzed by multivariate analysis. When we combined the gestational ages of all preterm infants grouped together, compared with those born full term and post-term, all findings lost significance (Table 3).
Caesarean Delivery and Prematurity
Children born via Caesarean section who were also born prematurely were not more likely to have a higher prevalence of FGIDs (P = 1.0000) (Table 4).
To our knowledge, this is the first published study in Latin America to evaluate whether the mode of delivery and length of gestation influence the development of FGIDs in children and adolescents. This is important as gut microbiota varies with dietary habits and environmental factors among regions (11).
Altered intestinal microbiota has been found in children and adults with FGIDs (12) and those born via Caesarean section and prematurely. It has been proposed that microbial dysbiosis could add to the development of IBS by altering the mucosal immune response and intestinal motility, and increasing visceral sensitivity (13). Lower abundance of potentially beneficial bacteria (Bifidobacterium and Lactobacillus) has been noted in patients with IBS (14). Infants born via vaginal delivery appear to become colonized by their mother's bacteria, including Lactobacillus, Bifidobacterium, and Bacteroides(15). On the contrary, infants born via Cesarean delivery are commonly exposed early to potentially pathogenic bacteria such as Klebsiella, Enterococcus, and Clostridium, and exposure to pathogenic bacteria has been linked to the development of IBS (14,15). Infants born premature have a significantly higher incidence of antibiotic exposure compared to infants born full term, which can result in alterations of the gut microbiome (16) including depletion of microbiota diversity (17). Multiple studies have also shown an association between the use of antibiotics and functional abdominal pain disorders in children and adolescents (18,19). Antibiotic use is a risk factor for functional bowel complaints in children and adults (18). Antibiotic exposure during the first 2 years of life has been associated with an increased risk for functional abdominal pain among pre-teen girls who were exposed to antibiotics during the first 2 years of life (19). Moreover, premature infants also have longer hospital stay, higher rates of tube feedings, and psychological and physical stressors including exposure to noxious stimuli that could increase the risk of developing aberrant pain pathways and visceral hyperalgesia (20).
Considering that early alterations in gut microbiota are common amongst infants born via Cesarean section and premature birth, and that premature infants have additional risk factors that could also potentially predispose to the development of FGIDs, we hypothesized that infants delivered via Cesarean and those born prematurely would have an increased risk for developing FGIDs. However, we found no differences in the prevalence of FGIDs between those born via Cesarean section or via vaginal delivery. We also found no significant increase in the prevalence of FGIDs among those born prematurely with the exception of a modest increase in functional nausea among infants born between 28 and 32 weeks. The statistical significance was, however, lost in multivariate analysis. The possible relevance of these findings should be further investigated because our study was not powered to study this specific association. Functional nausea is a new diagnosis of the Rome IV criteria and therefore at this time there are not enough studies focused at risk factors for this diagnosis.
Despite the negative results of our study, we may not exclude that the association between Caesarean section and prematurity with FGIDs still exists. The influence of Caesarean section and prematurity on the incidence of FGIDs in infants has not been studied. Thus, we may not exclude that a study focused on a shorter interval of time between birth and time of assessment could have resulted in different results. It is possible that the influence of mode of delivery and time of gestation is initially present but is lost with time as multiple other factors such as environmental exposure, family dynamics, infections, diet, and use of medications during the early years temper its effect.
There were limitations to our study. Multiple confounding variables that have not been explored could have influenced our results. We have decided against assessing some variables due to concerns of parental recall bias. For example, parents may not easily recall whether their child was exposed to antibiotics as an infant or be able to accurately estimate infant exposure to noxious stimuli during hospitalization. Parents may not accurately recall length of hospital stay or be less inclined to report lack or short period of breast-feeding. Further examination of these confounding variables including type and time of feedings could improve our understanding of the role of early life events in the development of FGIDs.
In conclusion, our findings provide evidence that Cesarean delivery and prematurity are not risk factors for the development of FGIDs. Although there are differences in the types of bacteria that infants delivered via Cesarean section are exposed to compared to infants born vaginally, we found no differences in the prevalence of FGIDs between these 2 groups. Further research with a larger data set is warranted to investigate the relationship between prematurity and FGIDs. In addition, studies investigating the possible role of mode of delivery, length of gestation, and feeding in the first years of life are warranted.
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