Introduction

Asthma is one of the leading causes of chronic respiratory disease-related death globally [1] and is the most common noncommunicable disease. Globally, asthma affects about 300 million people [2], and the prevalence of asthma in children and adolescents is approximately 10% [3]. Patients often suffer recurrent episodes of wheezing, coughing, chest tightness and other symptoms [4, 5]. Chronic airway inflammation is a common feature of asthma. It not only causes adverse physical and psychological feelings, but also lowers the quality of life and shortens life expectancy. Asthma is caused by the interaction of genetic and environmental factors [6]. Lung function defects, respiratory infections, and other factors are associated with the development of asthma [7]. Fetal exposure during pregnancy (such as cesarean section (CS) [8]) has been suggested as one of the determinants of immune system development [9].

In recent decades, the incidence of CS worldwide has continued to rise. The global CS rate is expected to increase to nearly 30% in 2030 [10]. Although rational use of CS in critical settings can reduce maternal and neonatal mortality and morbidity [11], excessive use of CS is not beneficial to the mother or the infant and will cause some waste of resources [12,13,14]. Even if the application of CS is mature, the short or long-term health damage of CS to infants is worth exploring, such as obesity [12, 15], type 1 diabetes [16, 17], and leukemia [29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57] were finally included in the systematic review and meta-analysis. A detailed PRISMA flowchart is shown in Fig. 1.

Fig. 1.
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PRISMA retrieval procedures flow chart

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Study characteristics and quality assessment

Table 1 shows the basic characteristics of all included articles. Thirteen prospective cohort studies and twenty-two retrospective cohort studies were included in the systematic review and meta-analysis of the association between CS and asthma. These selected studies were distributed across different regions, with four studies conducted in Asia, twenty-three studies in Europe, five studies in North America, and three studies in Oceania. Participants were diagnosed with asthma between the ages of 0–18. Most articles adjusted for confounding factors such as sex, gestational age, birth weight, maternal age, and parity. Supplementary Table 2 provides details about the source of the participants, birth period, follow-up time, and asthma registry. The quality of the included studies was assessed by the NOS checklist with a score of ≥ 6. Detailed results of the quality assessment are provided in Supplementary Table 3.

Table 1 Characteristics of all the studies included in the systematic review and meta-analysis
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Association of cesarean section and asthma

Thirty-five articles reported on the association between mode of delivery and asthma. The results showed that the incidence of asthma was higher in offspring born via CS than those born via VD (OR = 1.18, 95%CI = 1.13–1.23, P < 0.001, I2 = 82.3%) (Fig. 2). To explore the sources of heterogeneity, the following subgroup analyses were designed (Table 2). First, subgroup analysis based on CS type showed that offspring born via elective CS (OR = 1.18, 95%CI = 1.11–1.25) and emergency CS (OR = 1.18, 95%CI = 1.10–1.27) had a higher incidence of asthma than the VD group, which was consistent with the overall results. According to sex-grouped data, female offspring born via CS (OR = 1.26, 95%CI = 1.13–1.42) had a higher incidence of asthma compared to the VD group, but there was no difference in males (OR = 1.07, 95%CI = 0.94–1.22). According to the continental divisions in the different study regions, there was no difference in asthma incidence between Asian populations born via CS (OR = 1.17, 95%CI = 0.97–1.42) and offspring born via VD. Those born via CS in Europe, North America and Oceania all had a higher incidence of asthma than the VD group (P < 0.05).

Fig. 2.
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Forest plot of the association between cesarean section and asthma (P < 0.001)

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Table 2 Subgroup analyses of the association between cesarean section and asthma
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Offspring born via CS had a higher incidence of atopic asthma (OR = 1.14, 95%CI = 1.11–1.18) compared to the VD group. The CS group had a higher incidence of persistent asthma (OR = 1.15, P = 0.063) than the VD group, but this difference was not statistically significant. Finally, in prospective cohort studies (OR = 1.19, 95%CI = 1.11–1.28) and retrospective cohort studies (OR = 1.17, 95%CI = 1.11–1.23), the incidence of asthma in offspring born via CS was higher than that in controls.

Publication bias and sensitivity analyses

The statistical results of the Begg’s funnel plot showed no potential publication bias in the forest plot of the relationship between mode of delivery and incidence of asthma (P = 0.066) (SFig. 1). After excluding articles one by one, sensitivity analysis showed stable results (SFig. 2).

Discussion

The purpose of this study was to investigate the statistical association between CS and asthma in children/adolescents, which was used to infer whether there is an effect of CS on asthma. The results of the systematic review and meta-analysis showed that children/adolescents born via CS were at increased incidence of develo** asthma compared to VD. Further subgroup analyses showed that the relationship between CS and asthma was not affected by CS type, asthma type, or cohort design. But the increased incidence of asthma in children/adolescents born via CS may be influenced by sex and region.

The etiology of asthma has not been determined, and some studies believe that both genetic factors and environmental factors affect the occurrence of asthma [6]. Most immune system dysplasia is caused by environmental factors [58], which is an important cause of the epidemic of noncommunicable diseases [59]. Herein, the possible mechanisms by which CS increases asthma incidence are speculated from the following aspects.

First, childbirth is one of the early exposures for newborns. As is known to all, newborns born via CS are exposed to a different external environment for the first time compared to VD. Neonates born via VD are primarily exposed to bacteria in and around the maternal birth canal, whereas neonates born via CS are predominantly exposed to external bacteria [60]. Animal studies have shown that CS affects the diversity and density of the intestinal flora [61]. Infants born with CS have reduced numbers of Bacteroides and microbial sphingolipids in their faeces, so infants are more susceptible to asthma [62].

Second, compared to VD, CS was considered to postpone the onset of breastfeeding and to shorten the duration of exclusive breastfeeding [63], which may result in infants having insufficient exposure to breast milk. Breast milk contains high amounts of immunoglobulin (Ig) A, glycans [64], bioactive enzymes, and hormones that benefit the development of the immature immune defense system [65]. Breast milk has been found to transfer airborne antigens to newborn mice. Due to the presence of transforming growth factor-β mediated by CD4 + T lymphocytes in breast milk, its signalling is dependent on T cells. This induces antigen tolerance in newborns and provides specific protection against some allergic airway diseases, such as asthma [66]. Moreover, adequate breastfeeding is thought to facilitate the growth of infants’ lungs [67]. Therefore, insufficient breastfeeding may increase the risk of asthma.

Third, CS increases the binding of the progeny dopamine D1-like-receptor [68]. The conduction signal of D1-like-receptor facilitate the activation of the B-cell activating transcription factor, thereby increasing the transcription of the retinoic acid receptor-related orphan receptor-γ-t, and promoting the differentiation of T helper cell (Th) 17. Correspondingly, more Th17 were found in the spleen cells of mice in the asthma group than in the control group [69]. Th17 participate in antigen-induced aggregation of neutrophils and eosinophils in the airways, which play an important role in asthma [70, 71]. Antagonizing D1-like-receptor will inhibit the Th17-mediated inflammatory response in the lungs [72], but this evidence has not yet been validated in humans.

Finally, infants born via CS exhibit higher DNA methylation of cord blood leukocytes [73]. DNA methylation has been shown to play an important role in fetal development and may be an important cause of susceptibility to certain diseases [74]. DNA methylation may alter the composition of immune cells by regulating gene expression, putting CS offspring at higher risk of asthma. Undesirable methylation may disrupt the balance of Th1 and Th2, thereby increasing the risk of immune disease, which may be a regulatory mechanism for allergic asthma [75]. Allergic asthma is also known as atopic asthma, and the subgroup results in this study show that CS may be a risk factor for atopic asthma.

Subgroup results showed that the incidence of asthma appears to vary by sex. Compared to VD, CS is a risk factor for asthma in female rather than in male. There may be three possible reasons for this. (1) Asthma is a heterogeneous condition that may be sex-specific. Biological differences in development in the womb may explain the sex differences in asthma incidence. Sex influences the physiology and development of the infant’s lungs [76, 77]. In addition, females will appear more asthma attacks and asthma symptoms compared to males, and bronchial hyperresponsiveness is more common in females [78]. Asthma attacks in female appear to be closely related to menstrual periods. Asthma symptoms worsen during ovulation and menstruation [79]. Asthma patients have high markers of inflammation during the menstrual cycle, so asthma may be associated with female physiological hormones [80]. (2) Female infants have better viability than male infants when faced with adverse birth circumstances such as prematurity [81], which may result in more female babies surviving than male infants. Thus, more female than male infants are registered as having asthma. This may be one of the reasons why no association was found between CS male offspring and asthma. (3) The number of relevant studies that could be included was small and the results were subject to some chance.

The prevalence of childhood asthma varies considerably between countries [82]. It is well known that the developed countries are mainly distributed in Europe. Of the studies included in this systematic review and meta-analysis, the largest number of studies, up to twenty-three, were conducted in Europe. Notably, these studies were carried out in developed countries. In addition, research in North America and Oceania was also carried out in developed countries. Our results show that infants born via CS have a higher incidence of asthma compared to VD births in Europe, North America, and Oceania. Interestingly, no such association was found in infants born in Asia. The following three reasons are considered: (1) race may have influenced the onset of asthma. The relative prevalence of asthma varies by ethnic group [83]. (2) Developed countries have a high level of medical care and pay more attention to the health damage caused by diseases. People actively seek medical treatment, which is conducive to the diagnosis of diseases. This may be one of the reasons for the largest increase in asthma incidence in developed countries [84]. Develo** country studies make up the majority of Asian regional studies. Disease diagnosis rates in develo** countries may be lower due to a variety of factors. (3) And it should also be considered that the criteria for performing CS may vary between develo** and developed countries.

Reviewing past systematic review and meta-analyses, Keag et al.concluded that CS was associated with asthma in children under 12 years of age. However, the number of studies included in this meta-analysis is relatively small [12]. A subsequent study focused on the relationship between CS and asthma. In addition to cohort studies, this meta-analysis included case–control studies and cross-sectional studies [85], which may have reduced the level of evidence for the results. Another meta-analysis on a European population took into account the heterogeneity of results and concluded that CS could not be clearly recognized as a risk factor for asthma in children [22].

The strengths of this study are as follows: (1) the number of included studies was comprehensive. It was an update and supplement to previous meta-analyses with detailed subgroup analyses. (2) This article was a systematic review and meta-analysis based on cohort studies. The high certainty of the evidence from the cohort studies contributed to the credibility of this study. However, there are some limitations: (1) there was selection bias and follow-up bias in the original studies. (2) The number of relevant studies in some subgroups was small.

Conclusions: CS seems to be associated with asthma in children/adolescent offspring compared to VD. However, the result has a relatively high degree of heterogeneity and require further validation. Subgroup analyses showed that sex may influence the relationship between CS and asthma, with the risk of asthma in CS offspring only present in females. The risk of CS for asthma appears to differ across regions. CS may be related to childhood/adolescent asthma in populations in Europe, North America, and Oceania.