Children delivered by cesarean section had increased risk of current asthma at 36 months of age. This increase in asthma among children delivered by cesarean section was higher among children of nonatopic mothers than among children of atopic mothers. In contrast, no increased risk of wheezing or recurrent LRTIs was identified. The findings were similar among children delivered by acute and elective cesarean section and were seemingly not due to an indirect association with breastfeeding or day care attendance. The increase in the rate of asthma among children delivered by cesarean section was similar to that identified in 2 previous meta-analyses (15
). To our knowledge, the present study is the largest pregnancy cohort study in which the association between delivery by cesarean section and development of wheezing and asthma was examined while controlling for a wide range of influencing factors, as well as the first in which the association between delivery by cesarean section and recurrent LRTIs was examined.
Five large studies have previously identified increased wheezing or asthma in people delivered by cesarean section (8
), whereas 2 studies found no such increase (10
). Among studies that distinguished between age of disease classification (12
), several have indicated stronger associations among children who had asthma at a younger age, and one study found the association exclusive to asthma before 36 months of age (13
). In contrast, one meta-analysis found a weaker association between delivery by cesarean section and asthma in studies in which subjects younger than 10 years of age were included (15
), whereas another meta-analysis found reduced heterogeneity between studies when only pooling results from studies in which the subjects were younger than 18 years of age (16
). Some studies found an increase in asthma in children delivered by cesarean section only among girls (35
). Two studies identified a stronger association between cesarean section and asthma among children of atopic mothers (12
), whereas one found a stronger association among children of nonatopic mothers (37
), similar to that identified in the present study. Furthermore, previous studies have indicated that the increase in asthma among those delivered by cesarean section is higher among children of younger gestational age (14
), but differences by gestational age were not statistically significant in the present study. Finally, some studies found stronger associations among children delivered by acute cesarean section as opposed to elective cesarean section (14
), whereas others found no such difference (9
The hygiene hypothesis suggests that increased disease development among children delivered by cesarean section could be the result of delayed gut colonization due to lack of contact with maternal vaginal fecal flora, resulting in an altered immune system development (2
). Children delivered by elective cesarean section are hypothesized to have less exposure to maternal vaginal fecal flora compared with those delivered by acute cesarean section (14
). Considering this hypothesis, the association between cesarean section and the development of respiratory symptoms and disorders would be expected to be stronger among those delivered by elective cesarean section, a theory not supported by the findings of previous studies or the current study. Only about 37% of children who have problems with wheezing early in life have persistent wheezing symptoms at 10 years of age (41
), whereas atopic manifestation usually occurs at school age (42
). Differences in the association between cesarean section delivery and asthma between age groups might therefore reflect the different asthma phenotypes (42
Children delivered by cesarean section have increased neonatal respiratory morbidity (43
), which is also linked to the development of wheezing and asthma (5
). The shorter gestational age and increased neonatal respiratory morbidity among children delivered by cesarean section reflect the importance of a suboptimal intrauterine environment that is influenced by maternal age, smoking, chronic conditions, pregnancy complications, and prepregnancy BMI (46
), factors known to also increase the likelihood of wheezing and asthma (18
). Pregnant women who indicate that they prefer to give birth by cesarean section might be mothers with increased health awareness. For example, women with poorly controlled asthma or higher socioeconomic status could be more likely to want to deliver by cesarean section (48
). The stronger association between cesarean delivery and asthma among children of nonatopic mothers might indicate that delivery by cesarean section is not an important risk factor in children with a hereditary predisposition. The tendency for a stronger association between delivery by cesarean section and development of asthma among children of lower gestational age could reflect an underdevelopment of the lungs, decreased respiratory health, and an increased susceptibility to infections among children of lower gestational age (50
Strengths of the current study include the large sample size, prospective data collection, and wide range of factors for which we controlled. Only a few previous studies have been able to distinguish between acute and elective cesarean section, and no previous study has examined the association between cesarean section delivery and recurrent LRTIs. The present study controlled for several factors that previous studies had not been able to examine, including identification of the importance of maternal prepregnancy BMI, and we were also able to distinguish that the positive association between cesarean section delivery and asthma was not due to an indirect association with breastfeeding or day care attendance. The prospective data collection reduced the risk of recall bias and decreased the likelihood that mothers would differentially report information on potential confounders based on their child's disease status.
Several limitations also need to be addressed. Relying on maternal report of respiratory symptoms and disorders might have resulted in misclassification. The prevalence of maternal reports of a child's having asthma at 7 years of age in MoBa had a strong agreement with registered use of antiasthmatic medications in the Norwegian Prescription Database (51
). However, classification of asthma at 36 months of age might not be a good indication of asthma at school age. The frequency of wheezing episodes was not registered, making it difficult to address the severity of wheezing symptoms. Because women were recruited in the middle of pregnancy, it is unlikely that a selection bias based on cesarean section delivery and/or child respiratory disorders occurred at this point, as both events occurred after this time. However, the children with the necessary follow-up information for the present study included a lower proportion of deliveries by cesarean section. As mothers of children with respiratory symptoms and disorders might be less likely to have continued participation because of the burden of having a child with a chronic illness, a selection bias cannot be excluded. However, because of the substantial development of asthma medication and management over the last decades, most children experiencing asthma today have fewer and less severe asthma attacks.
In conclusion, children delivered by cesarean section might have an increased risk of current asthma at 36 months of age, especially children of nonatopic mothers. The findings were influenced by confounding factors, which increased the possibility of residual confounding. Factors that might have contributed to residual confounding include an underlying child pathology, epigenetic mechanisms, and maternal psychosocial factors. Further prospective studies should attempt to reexamine these relations in different age groups.