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Allergies have become an epidemic in industrialized countries . Food allergies and atopic eczema are often the first manifestations of allergic conditions to appear during the first year of life [2, 3], and these constitute risk factors for other allergies and asthma . Therefore, we need well-designed longitudinal studies, conducted in unselected populations, to increase our understanding of early-life risk factors for allergic diseases.
Caesarean section has often been suggested as a potential risk factor for allergic manifestations, compared with children born by vaginal delivery, due to delayed microbe colonization [5-18]. For example, caesarean section was associated with a moderately increased risk of asthma in two meta-analyses [5, 6]. However, reports from a large register-based study from Sweden  and a population-based cohort study from New Zealand  considered lack of exposure to vaginal microflora as an unlikely explanation for the association between caesarean section and asthma. Hospital delivery has also been associated with colonization of clostridium difficile , stimulating debate about whether this infection is either a marker of reduced colonization of other microbiota or a possible reason for allergic diseases [21, 22]. Three studies have found a positive association between caesarean delivery and sensitization or allergy to food items among healthy, full-term newborn infants [8-10, 12]. Two of them restricted their study population to offspring with a family history of allergy [8, 9, 12], which begs the question of a possible interaction between family history and mode of delivery. Yet, the association and its causal nature remain unclear [6, 11, 19-23].
The South Karelian Allergy Research Project (SKARP) is a population-based study comprising all children of a given age range and living in the same province. Data were collected by questionnaire and drawn from existing records on allergy tests that had been performed for diagnostic purposes [24, 25]. This study addresses the hypothesis that caesarean section is associated with the occurrence of allergy testing, positive test results and physician-diagnosed allergic manifestations up to 4 years of age. It also explores whether the possible effect of caesarean section is modified by parental allergies in a real-life epidemiological setting.
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Data on the mode of delivery were available for 3181 participating children, covering 98% of all those responding to the questionnaire and 67% of all those (N = 4779) who were initially invited to take part in the study (Fig. 1). Of those 3181 participants, 751 children (24%) had at least one allergy test taken by September 30, 2006. This percentage was similar (24%, N = 370) to the 1552 subjects for whom data on delivery were not available and whose parents had not refused the data linkage.
Overall, 17% of the children were born by caesarean section (Table 1). This proportion was higher for firstborn and preterm infants, those weighing <2500 g at birth and those breastfed for a short duration. It was also higher in the children whose mothers suffered from allergies. Mode of delivery seemed to be essentially independent of the gender of the child and maternal smoking.
The baseline occurrence of the different allergic outcomes by the age of 4 years varied from two to 10%. No clear difference was observed between caesarean section and vaginal delivery for any category of allergy in the cumulative incidence of allergy testing or of positive test results by 4 years of age (Table 2 and Fig. 2). Compared with children born by vaginal delivery, the adjusted relative incidence of positive allergy test (with 95% confidence intervals, CI) in children born by caesarean section was 1.14 (0.79, 1.65) for food, 1.16 (0.66, 2.05) for animal, 0.94 (0.46, 1.92) for pollen and 1.19 (0.87, 1.63) for any allergens. When the estimated rate ratios noted above were adjusted for selected covariates, they were all close to unity. Based on the location of the pertinent confidence limits at both sides of one, these findings do not provide adequate statistical support for the hypothesis that the mode of delivery would be associated with the outcome of interest. However, due to the relatively small numbers of cases included in our study, our results were too imprecise to rule out the possibility of such an association existing.
Table 2. Cumulative incidence (%, from Kaplan–Meier analyses) up to 4 years of age of first allergy test and of first positive test result, respectively, for different allergens, and the lifetime prevalence (%) of physician-diagnosed allergies and allergic conditions by mode of delivery. Estimated incidence rate ratios (RR) and prevalence odds ratios (OR) of respective outcomes for children born by caesarean section compared with those born by vaginal delivery (N = group size, n = number of cases, 95% CI = 95% confidence interval)
|Allergic manifestationa||Mode of delivery|
|Vaginal N = 2630||Caesarean N = 551||RRb/ORc (95% CI)|
|% (n)||% (n)|
|First test||18.7 (470)||19.0 (106)||1.05 (0.83, 1.32)b|
|First positive test||8.0 (200)||8.0 (47)||1.14 (0.79, 1.65)b|
|Physician-diagnosed||9.4 (245)||9.9 (54)||1.15 (0.80, 1.63)c|
|First test||12.1 (271)||13.5 (61)||0.97 (0.72, 1.33)b|
|First positive test||3.2 (71)||3.6 (18)||1.16 (0.66, 2.05)b|
|Physician-diagnosed||2.2 (56)||2.1 (11)||1.24 (0.59, 2.41)c|
|Pollen allergy (or hay fever)|
|First test||9.4 (201)||10.1 (45)||0.90 (0.63, 1.30)b|
|First positive test||2.4 (47)||2.4 (12)||0.94 (0.46, 1.92)b|
|Physician-diagnosed||3.2 (83)||3.4 (18)||0.90 (0.47, 1.59)c|
|Physician-diagnosed||18.7 (480)||19.3 (104)||1.00 (0.75, 1.31)c|
|Physician-diagnosed||4.6 (116)||4.5 (24)||0.96 (0.54, 1.61)c|
|Physician-diagnosed||2.4 (60)||3.2 (17)||1.12 (0.56, 2.10)c|
|Symptoms of asthma|
|Physician-diagnosed||9.8 (252)||13.9 (75)||1.37 (0.98, 1.90)c|
|Diagnosis of asthma|
|Physician-diagnosed||4.1 (106)||4.3 (23)||0.96 (0.53, 1.65)c|
|First test||25.1 (610)||27.0 (141)||1.10 (0.89, 1.35)b|
|First positive test||10.4 (254)||11.1 (61)||1.19 (0.87, 1.63)b|
|Physician-diagnosed||26.2 (686)||28.1 (154)||1.08 (0.85, 1.38)c|
Figure 2. Cumulative incidences of allergy testing and positive test results separately for animal (A), pollen (B), any food (C) and any allergens (D) according to mode of delivery (N = 3181). Solid line = vaginal delivery and dashed line = caesarean section.
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The adjusted odds ratios (with 95% CI) of the prevalence of physician-diagnosed allergic manifestations were 1.15 (0.80, 1.63) for food allergy, 1.24 (0.59, 2.41) for animal allergy, 0.90 (0.47, 1.59) for pollen allergy or hay fever, 1.00 (0.75, 1.31) for atopic eczema, 0.96 (0.54, 1.61) for allergic urticaria, 1.12 (0.56, 2.10) for allergic conjunctivitis, 0.96 (0.53, 1.65) for asthma, 1.37 (0.98, 1.90) for symptoms of asthma and 1.12 (0.87, 1.42) for any allergic manifestation. No evidence could thus be found for elevated odds of any of these outcomes in children born by caesarean section, when compared with children born by vaginal delivery (Table 2). Yet, the confidence intervals in these comparisons were also relatively wide.
Insufficient evidence was found for a possible modification of parental allergies on the effect of caesarean section (data not shown). However, evaluation of the relevant interaction terms was based on too small numbers in the key subgroups for any adequate statistical precision.
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Our results did not provide adequate support for the hypothesis of a positive association between caesarean section and the emergence of allergic manifestations or sensitization during the first 4 years of life. Even though the baseline occurrence of the different allergic conditions varied from 2% to 10%, the relative contrasts between the caesarean section group and the vaginal delivery group were all very close to one, when adjusted for important potential confounders. However, many of the confidence intervals in our results were relatively wide. Therefore, this overall negative finding cannot rule out the possibility of caesarean section having some effects, albeit not very strong, on the risk of allergies and/or asthma.
The main strength of this study is the population-based longitudinal database  comprising both questionnaire and allergy test data. Unlike previous studies, we could describe the associations between the mode of delivery and several allergic outcomes in an unselected population in a real-life setting. This is also one of the largest studies ever conducted on this topic in unselected child populations [4, 5]. It also appears to represent the general population well. For example, the 17.3% of children born by caesarean section was close to the 16.6% reported for all of Finland in the year 2004 . In addition, the proportions of premature infants (5.3%) and of children with birth weights of <2500 g (3.8%) were also close to those in the whole country during 2004 (5.8% and 4.4%, respectively) . Another important strength of our data is that it included the exact dates of both allergy testing and positive test results, which enabled us to display the cumulative incidences of outcomes according to the mode of delivery and to apply survival methods in the data analysis.
As to the shortcomings of the study, we would first mention the fact that one-third of the parents invited to take part in the questionnaire survey did not respond. However, based on our findings in previous research  and in this study, this nonresponse does not seem to have negatively affected the representativeness of the final study population. Also, we find it reassuring that the overall percentage of the allergy tested children among the nonrespondents was not different from the percentage among the respondents. Selection bias would be an issue, if nonresponse and/or experiencing allergy testing were dependent both on the main risk factor and on the study outcomes. Such a joint dependency cannot be directly examined, though. Nevertheless, we find it unlikely that participation in the survey, and/or exposure to allergy testing, would be at all dependent on the mode of delivery when this dependence is considered as conditional on any indication for such a test being ordered. Indirect support for the latter standpoint is provided by the fact that the 4-year incidence of any allergy testing among the participants was only slightly higher for the caesarean section group than for the vaginal delivery group.
In the final study population, certain covariates were absent, but the percentage of missing values was clearly <10% for all of them. These missing data can hardly be considered to be dependent either on the mode of delivery or on the outcomes to such an extent that the estimates of interesting rate ratios or odds ratios would be seriously affected.
The heterogeneity of the test data obtained from several laboratories might have introduced some misclassification of the outcome, but it is unlikely that this would have affected the findings with respect to the mode of delivery and the other covariates considered. The same can be said about the variability in the timing of responding to the questionnaire and of the allergy tests, there apparently being no systematic differences between the caesarean section group and the vaginal delivery group.
The questionnaire method may perhaps be considered as the main weakness of our study. More accurate perinatal data could, in principle, be obtained from the Medical Birth Register of Finland. Unfortunately, we did not have resources for the necessary record linkage. However, parents are likely to recall the mode of delivery, duration of pregnancy and birth weight accurately. Moreover, most questionnaires were returned during a visit to the child health clinic and the public health nurse checked them and completed the relevant missing items from the documents or patient records kept at the clinic , thereby further improving the quality of the data. Thus, we have good grounds to believe that our perinatal data were not affected by recall bias. On the other hand, the questionnaire was the only feasible method of obtaining all the relevant information from a sufficiently large population. Many of our outcome variables, as well as the covariates describing parental allergies, mother's smoking and duration of breastfeeding, were only based on the questionnaires and would not be available from any register.
The questionnaire lacked more specific classification for caesarean section (e.g. elective or emergency) or vaginal delivery (e.g. use of forceps or vacuum extraction). During the years 2004 and 2005 , forceps were rarely used in Finland overall (0.1% of all deliveries) and in none of the deliveries in South Karelia. Thus, it is highly likely that forceps were only used for a handful of deliveries, at most, among the SKARP study participants. Moreover, in South Karelia, only 6.5% of singleton deliveries were assisted by vacuum extraction, 8.9% were assisted by elective caesarean sections, and 8.9% were subjected to emergency or urgent sections . Any analyses based on this more refined classification of deliveries, even if available, would have resulted in greater imprecision in the estimation and wider confidence intervals of the interesting relative effects in these subgroups in our study.
A further limitation was that the follow-up only lasted up to the age of 4 years, which is apparently too early to be informative for asthma and pollen allergy or hay fever, although quite sufficient for food allergies and atopic eczema. A longer follow-up would obviously have yielded a higher number of cases and narrower confidence intervals for all outcomes. As the age of the child at the end of the follow-up, and at the time of the questionnaire survey, was allowed for in the regression models, heterogeneity of ages of the study population only affected the precision of the results, but hardly caused any major bias.
A positive association between caesarean delivery and allergy or sensitization to food items has been reported in several studies [8-10, 12]. Our estimates did not disagree with these when taking into account the statistical error margins. However, none of those studies were based on an unselected population like ours. Moreover, the finding of Eggesbø et al.  was confined only to children with an allergic mother, the population studied by Laubreau et al.  comprised only offspring with a family history of allergy and Koplin et al.  could not confirm the association between caesarean section and egg allergy among children with a maternal history of allergy. In our population, the subgroup of children born by caesarean section and with parental allergies was too small for sufficiently precise evaluation of whether the effect of caesarean section would be different in children with such a family history than in other children. The authors of a meta-analysis  expressed concern about the possibility of publication bias explaining the reported positive association between caesarean section and food allergies. Also, the variability in the food allergens and the cut-off points used in different studies make any comparisons across different studies difficult. No association between caesarean section and inhalant atopy or eczema/atopic dermatitis could be found in the same meta-analysis  or in a population-based cohort from New Zealand , our observations being concordant with both of these reports.
There appears to be a discrepancy between the relative odds estimates for the history of symptoms of asthma and of physician-diagnosed asthma, both based on parental reports. However, when the error margins are taken into account, these do not conflict with each other. They are also statistically consistent with the results of two meta-analyses reporting a moderately increased risk of asthma among children born by caesarean section [5, 6] and with the previous Finnish studies on this topic [13, 14, 17]. A register-based Finnish Birth Cohort in 1990  and Northern Finland Birth Cohorts in 1985 and 1966 (NFBC1985 and NFBC1966) [13, 14] all reported that caesarean section was associated with the occurrence of diagnostic codes for asthma by the age of 7 years, with history of physician-diagnosed asthma or hospitalization due to asthma (49 cases) by the age of 7 years and with physician-diagnosed asthma (14 cases) in adulthood, respectively. In the study population of the NFBC1966, caesarean section was not found to be associated with atopy, hay fever or atopic eczema .
Our results are also well in accordance with the results of two population-based cohorts from Brazil  and with large population-based cohorts from Denmark  and from New Zealand , in which no association could be found between asthma and the mode of delivery. A large register-based Swedish study by Almqvist et al.  found that the association between elective caesarean section and use of asthma medication disappeared when they carried out a sibling control analysis. They also concluded that the indications of emergency caesarean section, rather than the mode of delivery or delayed microbial contact, are related to the use of asthma medication among the offspring. In the birth cohort from New Zealand , forceps assistance during vaginal delivery was associated with atopy and asthma at the ages of 13 and 32 years, but after adjustments, the positive association disappeared or was greatly weakened. Hancox et al.  suggested that some other background factors associated with the mode of delivery might act as more probable risk factors for atopic outcomes than the lack of microbial contact in conjunction with caesarean section. However, in our cohort, parental factors (allergies), maternal factors (e.g. mother's smoking, duration of breastfeeding) and foetal factors (e.g. measurements at birth) were included as covariates in the models.
In conclusion, our results do not, as such, provide sufficient support for the hypothesis that caesarean section would increase the risk of allergic manifestations or allergic sensitization in early childhood. As these results have a relatively wide margin of error, we cannot rule out the possibility that caesarean section having some effects, albeit not very strong, on the risk of allergies and/or asthma. Replication in other, and hopefully even larger, unselected populations and a longer follow-up period are required for a more reliable evaluation of the hypothesis.