A meta-analysis of 9,939 cases of T1D showed that C-section was associated with a higher risk of this childhood disease (OR: 1.19 [1.04–1.36]) after adjusting for gestational age, birth weight, maternal age, birth order, breastfeeding, and maternal diabetes (37). In an Australian study examining perinatal risk factors for T1D in children under 6 years of age, planned C-section was again shown to increase the risk of T1D (OR: 1.30 [1.01–1.69]) compared to vaginal delivery (38). Similarly, in a Scottish study of more than 320,000 children, the risk of T1D was also higher (adjusted OR: 1.35 [1.05–1.75]) in those delivered by planned C-section than in those born by unscheduled C-section. These children also had higher risk of death (all-causes) prior to 21 years of age (adjusted OR: 1.41 [1.05–1.90]) compared with vaginally born children (39). In contrast, a retrospective study in Denmark looked at the effect of C-section vs. vaginal delivery on chronic immune diseases in all children born from 1973 to 2012, using the Danish national registries. About 1.9 million children were studied and a significantly increased risk of asthma, systemic connective tissue disorders, juvenile arthritis, inflammatory bowel diseases, immune deficiency, and leukemia was observed in those born through C-section; however, they did not find any increased risk of celiac disease, psoriasis, or T1D (40). Similar observations were reported by Clausen et al., also in Denmark (41).

Studies have also suggested an association between C-section and the risk of celiac disease. In a population-based, case–control study of 11,749 Swedish children with biopsy-verified celiac disease and 53,887 age- and sex-matched controls, planned, but not emergency, C-section was associated with an increased risk of later celiac disease (adjusted OR: 1.15 [1.04–1.26]), compared with vaginally delivered children (42). Similarly, a retrospective study using the Danish national registries that included all children born in Denmark between 1997 and 2012 showed that those delivered by unscheduled C-section had an increased risk of ulcerative colitis (adjusted OR: 1.47 [1.02–2.12]) and celiac disease (adjusted OR: 1.52 [1.06–2.20]), whereas children delivered by elective C-section had an increased risk of lower respiratory tract infections and juvenile idiopathic arthritis. The effect of elective C-section was greater than the effect of acute C-section on asthma risk (43).

On the other hand, Bager et al. conducted a meta-analysis of 26 studies (23 cohort and 3 case–control studies) including approximately 1.3 million children, concluding that those born by C-section had higher risk of allergic rhinitis (OR: 1.23 [1.12–1.35]), food allergy or atopy (OR: 1.32 [1.12–1.55]), and asthma (OR: 1.18 [1.05–1.32]) (44). In a study by Black et al., children born by C-section were also more prone to develop asthma requiring hospitalization and to use salbutamol at 5 years of age (adjusted OR: 1.22 [1.11–1.35] and 1.13 [1.01–1.26], respectively), as compared to vaginally delivered children (39). Similar observations have been reported in other studies and meta-analyses (45). Data from 459 children born and cared for in the same maternity ward and followed for 3 years showed that C-section was a significant and independent predictor of food allergy (OR: 3.15 [1.14–8.70]) but not atopic dermatitis (46), confirming the conclusions of a recent systematic review (47). In a retrospective study of more than 7,500,000 Danish children, Kristensen and Henriksen also reported a higher risk of asthma in children born by both unscheduled and elective C-section (OR = 1.06 [1.02–1.10] and 1.24 [1.20–1.28], respectively) (43).

Researchers have also examined the impact of C-section on the subsequent development of obesity. In a Chinese study of 181,380 children, C-section was associated with a higher risk of being overweight after multivariate adjustment [in particular for prepregnancy maternal body mass index (BMI)] (OR: 1.13 [1.08–1.18]) (48). A small, multivariate analysis of 917 American children (~12 years of age) indicated that those born by C-section had approximately twice the likelihood of being obese (OR: 1.87 [1.19–2.95]) or overweight (OR: 1.86 [1.27–2.73]) than those who were born vaginally; this differed by gender, with males at greater risk (49). Recent systematic reviews and meta-analyses have drawn similar conclusions: Li et al. reported an increased risk of overweight/obesity in children (OR: 1.32 [1.15–1.51]), adolescents (OR: 1.24 [1.00–1.54]) and adults (OR: 1.50 [1.02–2.20]) born by C-section, and Kuhle et al. showed an increased risk of obesity after adjustment for maternal BMI (OR: 1.29 [1.16–1.44]) (50, 51). Analysis of mothers who had multiple births found that infants born by vaginal birth following a previous C-section were 31% less likely to become obese than infants born by a repeated C-section delivery. Moreover, within-family analysis showed that individuals born through C-section delivery were 64% more likely to be obese than their siblings born through vaginal delivery. The adjusted risk ratio for obesity among offspring delivered via C-section vs. those delivered vaginally was 1.15 [1.06–1.26] (p = 0.002). This association between delivery mode and obesity was stronger for children who were born by C-section among women without indications for cesarean delivery (52). These results, therefore, suggest that C-section affects obesity risk, independently of lifestyle and genetic factors.

Collectively, these results indicate that C-section is associated with increased risk of both metabolic diseases and chronic immune disorders during infancy.

Epidemiological data on T1D in Latin America are scarce (53). Higher rates of T1D are observed in countries with higher incomes, increased urbanization, and low Amerindian heritage. For example, a study of children under 14 years of age in Chile reported a lower incidence of T1D in the native aboriginal Mapuche population than in the Caucasian population (0.42 vs. 1.58 per 100,000; p < 0.001) (54, 55). Furthermore, a significant increase in the incidence of T1D was observed in the Chilean population from 2000 to 2004 (5.4 vs. 8.33 per 100,000; p < 0.04). Similarly, in Mexico a substantial increase (from 3.4 to 6.2 per 100,000) in the incidence of T1D was reported in children under 19 years of age from 2000 to 2010 (56). These studies indicate that the incidence of T1D has increased recently in Latin America.

Data from the International Study of Asthma and Allergies in Childhood showed that the prevalence of asthma or allergic disease ranged from 18 to 27% in Brazil, Uruguay, Paraguay, and Peru; these percentages are similar to those reported in developed countries, which are most affected by this disease (such as Western Europe) (57). However, these incidence rates are growing (+0.32%/year), and are accompanied by mortality rates (primarily due to bronchial asthma) that reach 5.6 per 100,000 in some countries, such as Mexico and Uruguay (57). Asthma is more frequent in urban, low-income populations, mainly due to the accelerated pace of urbanization and migration, the adoption of a westernized lifestyle, and environmental changes (increasing exposure to allergens and indoor/outdoor pollutants). Similar trends have been reported in regards to the incidence of food allergies in Latin America (58, 59).

The prevalence of obesity has increased significantly in Latin America, with about 57% of the adult population classified as overweight and 19% as obese (60, 61). The highest rates of childhood obesity are currently found in Chile (23% in 6-year-olds), and the lowest in Peru (1.8% in children <5 years of age) (62, 63). In Mexico, increased incidence of overweight/obesity has particularly affected adolescent girls and women, with an annual increase of about 1.5% from 1988 to 2012; however, incidence rates have increased much slower for preschoolers (0.3% per year; 1988–2012) and men (0.7% per year; 2000–2012) (64). In Colombia, from year 2005 to 2010, the proportion of individuals classified as overweight increased from 13.9 to 17.5% in children aged 5 to 17 years of age (62). In Brazil, the prevalence of obesity in children and adolescents has risen 240% in the past two decades (65); a similar increase has been observed in Chilean children (66).

While increased C-section rates in Latin America are not solely responsible for the increasing incidence of asthma, food allergies, obesity and T1D in the region, it is nevertheless a contributing factor. Accordingly, decreasing the number of unnecessary C-section surgeries could eventually attenuate the burden of these diseases.

C-section influences the establishment of gut microbiota in the newborns, thus affecting their exposure to bacterial antigens. Bacterial transmission from mother to newborn is currently considered a crucial factor for the establishment of the gut microbiota, which in turn shapes host immune responses (67). In fact, intestinal bacteria are involved in the development of gut-associated lymphoid tissues (GALT), the induction of oral tolerance, and (in rabbits) the diversification of the pre-immune antibody repertoire. In addition, animal studies have shown that an altered (by antimicrobials) gut microbiota early in life affects host physiology, through increased bodyweight and adiposity (68–70). Interestingly, these effects were more pronounced if this alteration occurred prior to weaning, suggesting the presence of a critical period during which an altered gut microbiota can impact the host’s health (68).

It is generally accepted that the fetus grows and develops in a sterile environment within the uterus, and that its passage through the birth canal during delivery is the baby’s first exposure to microorganisms. The pioneering bacterial communities that colonize the intestine originate primarily from the maternal vaginal and fecal microbiota in the case of vaginal delivery and from the mother’s skin microbiota in the case of C-section delivery. In the case of vaginal delivery, this community is primarily composed of facultative anaerobic bacteria, including Enterococcus, Staphylococcus, and enterobacteria, which consume the oxygen present in the intestinal lumen, assisting in the creation of an anaerobic environment that strictly anaerobic bacteria can colonize. Accordingly, at the end of the infant’s first week of life, the gut microbiota of a breastfed newborn is dominated by Bifidobacterium sp., with lower counts of Bacteroides sp., Clostridium sp., and lactic acid bacteria. The emergence of this Bifidobacterium-dominated microbiota is favored by the significant quantity of oligosaccharides (10–12 g/L) and other bifidogenic compounds (nucleotides, casein-derived glycomacropeptide) contained in breast milk (71, 72). The diversity of the infant gut microbiota increases gradually when solid foods are introduced, eventually reaching a stable adult-like microbiota at 2–3 years of age (73). Various factors influence the gut’s colonization, such as the use of and type of formula, as well as genetic, environmental, and lifestyle factors (73–75).

C-section alters bacterial colonization due to the fact that the fetus has no direct contact with the maternal vaginal/fecal microbiota during delivery, and as antimicrobials are frequently administered during surgery (76). Dominguez-Bello et al. observed that the bacterial composition of meconium samples from vaginally delivered newborns was similar to that of the vaginal microbiota of their mother; in contrast, meconium from newborns delivered by C-section was most similar to the maternal skin microbiota (dominantly composed of Streptococcus spp., Staphylococcus spp., and Propionibacterium spp.) (77). In addition, delivery mode has also been shown to influence the bacterial composition of breast milk, which is another important early bacterial source (78, 79). C-section delivery delays gut colonization by Bifidobacterium, Lactobacillus, and perhaps most importantly Bacteroides spp. Establishment of these bacteria is thus delayed, and typically mirrors that of a vaginally born infant only at around 6 months of age (80); however, some studies report that residual dysbiosis may persist for longer, until 2 or even 7 years of age (Table 2) (81, 82).

Although many studies have reported gut dysbiosis in patients with asthma, allergies, obesity or T1D (87), few studies have examined alterations in the postnatal microbiota of infants that go on to develop one of these pathologies, and those that exist mostly focus on allergies (Table 3). Various microorganisms that colonize the infant gut early in life, such as Bifidobacterium (88–91), Lactobacillus (90, 91), Enterobacteriaceae, and Clostridium (92), have been associated with the subsequent development of allergies. Although no specific microorganism has been clearly identified as either protective or inductive, various studies point to Clostridium difficile as favoring allergy development. In fact, colonization of the gut by this opportunistic pathogen is accompanied by disruption to the microbiota prior to the onset of allergic disease. As previously stated, various studies have described lower microbial diversity in children who subsequently developed allergies. One study showed that atopic eczema was preceded by decreased microbial diversity, specifically affecting the genus Bacteroides (93). It is possible that a more diverse gut microbiota is more efficient in improving the maturation of the immune system and reducing the risk of chronic immune disorders (94).

A longitudinal study analyzing the gut microbiota of infants from birth to 7 years of age, showed that those who became overweight at 7 years harbored significantly fewer Bifidobacterium sp. at 6 and 12 months of age compared with children who were normal weight at 7 years of age (101). More longitudinal studies evaluating the development of the early gut microbiota and its impact on the development of obesity, T1D, and food allergy are necessary to confirm whether alterations in the microbiota’s composition and/or a delay in the colonization process precedes the development of these diseases.

Decreased levels of intestinal Bacteroides spp. associated with C-section delivery are significant, as this microorganism strongly influences host physiology and metabolism. Studies in germ-free mice indicate that Bacteroides thetaiotaomicron participates in maintaining gut barrier function by increasing epithelial expression of the small proline-rich protein 2A, a polymeric immunoglobulin receptor, and matrilysin, a matrix metalloproteinase involved in defensin activation in Paneth cells (102, 103). The combination of Bacteroides fragilis and Bacillus subtilis consistently promoted GALT maturation in the rabbit appendix and led to the development of the pre-immune antibody repertoire, as reflected by increased somatic diversification of VDJ-Cμ genes in appendix B cells (104). Bacteroides species have also been implicated in the improvement of gut immunity and inflammatory response, by stimulating the plasmocyte production of secretory IgA (105). A polysaccharide A-expressing strain of B. fragilis also suppressed the release of the pro-inflammatory cytokine IL-17 in the intestine (106). Interestingly, adult mice born by C-section showed a lower proportion of Foxp3⁺ regulatory T cells and tolerogenic CD103⁺ dendritic cells, along with lower IL-10 expression in mesenteric lymph nodes and the spleen, suggesting negative long-term systemic effects of C-section delivery on the immune system of these animals (107).

Collectively, these results suggest that high levels of Bacteroides sp. (and eventually Bifidobacterium) present in the infant gut during the first 6 months following vaginal delivery exert health-promoting effects by favoring the maturation of GALT, mucosal immunity and oral tolerance, and reducing the risk of immune and metabolic disorders during infancy. On the contrary, for infants born by C-section delivery, the absence (or low abundance) of these microorganisms during this important physiological window of development appears to result in disturbances of immune homeostasis and a higher risk of developing metabolic and immune disorders later in life.