Abstract
Background
Cesarean delivery may alter neonatal immune responses and increase the risk of atopy. Studies of the relation between cesarean delivery and allergic diseases in children not selected on the basis of a family history of atopy have yielded inconsistent findings.
Objective
To examine the relation between birth by cesarean delivery and atopy and allergic diseases in children at risk for atopy.
Methods
We examined the relation between mode of delivery and the development of atopy and allergic diseases among 432 children with parental history of atopy followed from birth to age 9 years. Asthma was defined as physician-diagnosed asthma and wheeze in the previous year and allergic rhinitis as physician-diagnosed allergic rhinitis and naso-ocular symptoms apart from colds in the previous year. Atopy was considered present at school age if there was >=1 positive skin test or specific IgE to common allergens. Stepwise logistic regression was used to study the relation between cesarean delivery and the outcomes of interest.
Results
After adjustment for other covariates, children born by cesarean section had twofold higher odds of atopy than those born by vaginal delivery (OR=2.1, 95% CI=1.1–3.9). In multivariate analyses, birth by cesarean section was significantly associated with increased odds of allergic rhinitis (OR=1.8, 95% CI=1.0–3.1) but not with asthma.
Conclusions
Our findings suggest that cesarean delivery is associated with allergic rhinitis and atopy among children with parental history of asthma or allergies. This could be explained by lack of contact with the maternal vaginal/fecal flora or reduced/absent labor during cesarean delivery.
Clinical Implications
Potential development of allergic diseases should be considered as a potential risk of cesarean delivery among children with parental history of atopy.
Capsule Summary
Cesarean delivery may lead to an increased risk of allergic rhinitis and atopy in children with parental history of atopy.
Keywords: Cesarean delivery, allergic rhinitis, atopy, childhood
INTRODUCTION
Atopic diseases such as atopic asthma, allergic rhinitis, and eczema are a major public health problem worldwide1. Perinatal exposures may have a role in the pathogenesis of atopic diseases such as asthma and allergic rhinitis, which often begin in early childhood2.
In the United States, the percentage of children born by cesarean delivery increased from 23% in 1990 to 28% in 20033. Compared with vaginal delivery, birth by cesarean section leads to long-lasting changes in the neonatal intestinal flora4,5, which have been associated with atopy and/or allergic diseases in some studies6 but not in others5. Among children unselected for parental history of atopy, birth by cesarean section has been associated with an increased risk of asthma and/or atopic diseases in some studies7,8,9,10,11,12,13 but not in others 14,15,16,17.
To date, there has been no longitudinal study of the relation between birth by cesarean section and atopy and allergic diseases at school age among children at high risk for atopy. We examined the relation between birth by cesarean section and atopy and atopic diseases (asthma and allergic rhinitis) among children with parental history of atopy followed from birth to age 9 years.
METHODS
Study Population
Subject recruitment for the Epidemiology of Home Allergens and Asthma Study has been previously described in detail.18 In brief, subjects were recruited between September 1994 and August 1996. Eligibility criteria included living inside route 128 (which encircles the Boston Metropolitan Area), maternal age ≥18 years, parental ability to speak either English or Spanish, and a history of asthma or allergies in either parent. Exclusion criteria included gestational age of less than 36 weeks, hospitalization in the neonatal intensive care unit, or the presence of a congenital anomaly.
After obtaining written informed consent, a home visit was conducted at age 2 to 3 months and a questionnaire concerning demographics, home characteristics, environmental exposures, tobacco use and health outcomes was given by trained research assistants. Starting at age 2 months, a telephone questionnaire (modified from the American Thoracic Society-Division of Lung Disease Questionnaire)19 was administered by trained research assistants to the child’s primary caregiver until the age of 2 years. Afterwards, interviews were conducted every 6 months. Seven of the 505 children enrolled in the study were excluded because they were followed for less than 5 months during their first year of life. The study was approved by the Institutional Review Board of Brigham and Women’s Hospital.
Perinatal Variables
Information on mode of delivery and other perinatal variables was extracted from the maternal and neonatal medical records shortly after delivery. For data analysis, mode of delivery was considered as a binary (cesarean vs. vaginal) variable. Birth weight and gestational age were used as continuous and categorical variables.20 Head circumference data was missing for 21% of the participating children and was thus not included in the analysis.
Definition of Other Variables
Additional variables considered for inclusion in the multivariate analysis included sex, annual household income21, child’s ethnicity 21, number of older siblings, maternal age at delivery, gestational age 20, maternal asthma (ever and current), paternal asthma (ever and current), in utero smoke exposure, average number of cigarettes smoked by adults in the household per day, breast feeding 22, day care attendance in the first year of life 23, antibiotic use in the first year of life 24, bottle feeding in the crib or bed prior to sleep 22, physician-diagnosed illnesses of the upper (sinusitis and recurrent [≥3 episodes] of nasal catarrh) and lower (pneumonia, bronchiolitis, bronchitis, and croup) respiratory tract in the first year of life 25, and levels of dust mite allergen and endotoxin in house dust at age 2 to 3 months 26. The methods used to collect house dust samples and quantify levels of dust mite allergen (in the child’s bed) and endotoxin (in the family/living room) have been previously described 26–29.
Assessment of Allergic Sensitization
At a mean age of 7.4 years (range, 6.5 to 10.1 years), allergy skin testing was performed in 248 children and IgEs specific to common allergens were measured in an additional 23 children. Skin prick testing was performed on the volar aspect of the lower arms using extracts for cat dander, dog dander, mouse epithelia, cockroach (Blatella germanica), dust mite (Dermatophagoides pteronyssinus and Dermatophagoides farinae), ragweed, mixed trees, mixed grasses, and molds (Alternaria, Aspergillus, Cladosporium, and Penicillium)(Hollister Steir Labs, Spokane, WA). Histamine was used as a positive control and glycerinated saline as a negative control. Skin tests were read as positive if the mean diameter of the wheal was ≥3 mm after subtraction of the saline control wheal.
UniCAP 250 (Pharmacia & Upjohn, Kalamazoo, MI) was used to assay for specific IgE to the above allergens in the 23 children who refused skin prick testing. IgE values to specific allergens were considered positive when ≥ 0.35 IU/ml.
Definition of Outcomes
At age 9 years, asthma was defined as physician-diagnosed asthma and at least one episode of wheezing in the previous year, and allergic rhinitis as physician-diagnosed allergic rhinitis and a history of nasal discharge or sneezing apart from colds in the previous year.
Atopy (sensitization to 1 or more allergens) was primarily defined as at least one positive skin tests or specific IgE to the tested allergens at school age 26. In exploratory analyses, we subdivided atopy into two categories: sensitization to 1 or more perennial allergens and sensitization to 1 or more seasonal allergens, and considered the degree of atopy (different categories for the number of positive skin tests or specific IgEs [e.g., 0, 1–2, ≥3) to the allergens tested.
For the longitudinal analysis of repeated measures of wheeze, wheeze was considered present at any time point between ages 12 to 108 months if the child’s care taker reported “wheezing or whistling in the chest” since the previous visit.
Statistical Analysis
Bivariate analyses were performed using chi-squared or Fisher’s exact tests for categorical variables, and two-sided t tests or Wilcoxon tests for pairs of categorical and continuous variables, as appropriate. Stepwise logistic regression was used to study the relation between mode of delivery and the outcomes of interest (asthma, allergic rhinitis, and atopy) while adjusting for potential confounders. The final models included variables that were significant at P <0.05 or that caused a change in the estimated measure of effect (odds ratio) ≥10%. Selected interactions were examined after the final models were chosen.
To assess the relation between mode of delivery and childhood wheeze, we performed a longitudinal analysis of the relation between birth by cesarean section and repeated measures of any wheeze between ages 1 and 9 years. For that analysis, we used proportional hazard models, with repeated events on the same child being handled by the method of Andersen and Gill 30 and adjustment for correlations between these repeated events handled by methods described by Therneau and Grambsch 31. To examine age-dependent associations, we calculated interaction terms between the age of the children at each survey and the variables in the model.
RESULTS
The characteristics of the 498 study subjects have been described in detail elsewhere 32,24. Of the 498 participating children, 432 (87%) were followed up to age 9 years and 271 (54%) had an assessment of allergic sensitization. Children who did not have an assessment of allergic sensitization or who were not followed up to age 9 years were more likely to be of non-white ethnicity, to live in households with an annual income of <$30,000, and to have more than one sibling than children who had an assessment of allergic sensitization or who were followed up to age 9 years (Table 1). There were no significant differences in mode of delivery, birth weight, or gestational age between children who did and did not have an assessment of allergic sensitization. There were no significant differences in mode of delivery, birth weight, or gestational age between children who were and were not followed up to age 9 years.
Table 1.
Characteristics of Participating Children
| Variable | At baseline $ (n=498) | At 9 years of follow-up $ (n=432) | Children with assessment of allergen sensitization $ (n=271) |
|---|---|---|---|
| Number, (percentage) | Number, (percentage) | Number, (percentage) | |
| Female sex | 230 (46.2) | 195 (45) | 116 (43) |
| Household income <$30,000 | 45 (9.3) | 24 (5.7)* | 13 (5)* |
| Ethnicity | |||
| White | 375 (75.3) | 344 (79.6)* | 219 (81)* |
| Black | 60 (12.1) | 37 (8.6)* | 23 (9)* |
| Hispanic | 28 (5.6) | 19 (4.4) | 11 (4) |
| Asian and other | 35 (7.0) | 32 (7.4) | 18 (7) |
| Caesarean delivery | 114 (22.9) | 102 (23.6) | 65 (24.0) |
| -Scheduled | 27 (5.4) | 24 (5.6) | 16 (5.9) |
| -Nonscheduled | 86 (17.3) | 77 (17.9) | 48 (17.8) |
| Quartiles of birth weight (kg) | |||
| 1.84 to <3.18 | 125 (25.2) | 106 (24.6) | 67 (24.7) |
| 3.18 to <3.46 | 126 (25.4) | 108 (25.1) | 65 (24.0)) |
| 3.46 to <3.79 | 122 (24.6) | 108 (25.1) | 68 (25.1) |
| 3.79 to <4.91 | 124 (25.0) | 109 (25.3) | 71 (26.2) |
| Season of birth | |||
| Spring | 144 (28.9) | 127 (29.4) | 86 (31.7)* |
| Summer | 110 (22.1) | 94 (21.8) | 58 (21.4)) |
| Fall | 120 (24.1) | 106 (24.5) | 68 (25.1) |
| Winter | 124 (24.9) | 105 (24.3) | 59 (21.8) |
| Gestational Age <38.5 weeks | 104 (20.9) | 87 (20.1) | 60 (22.14) |
| Maternal history of asthma | 152 (30.5) | 125 (28.9) * | 76 (28.0) |
| Number of siblings in the child’s home | |||
| 0 | 228 (45.8) | 215 (49.8)* | 136 (50.2)* |
| 1 | 176 (35.4) | 147 (34.0) | 93 (34.3) |
| 2 or more | 94 (18.9) | 70 (16.2)* | 42 (15.5)* |
| >= 3 episodes of nasal catarrh in the first year of life | 421 (84.5) | 365 (84.5) | 229 (84.5) |
| Physician-diagnosed bronchiolitis in the first year of life | 65 (13.1) | 52 (12.0) | 35 (12.9) |
| Physician-diagnosed croup in the first year of life | 57 (11.5) | 47 (10.9) | 30 (11.1) |
| Quartiles of endotoxin (EU/mg) | |||
| 2.14–52.5 | 100 (24.9) | 84 (24.1) | 50 (22.6) |
| 52.5–79.9 | 100 (24.9) | 90 (25.8) | 53 (24.0) |
| 80.48–125.59 | 101 (25.2) | 88 (25.2) | 60 (27.2) |
| 125.6–713.2 | 100 (24.9) | 87 (24.9) | 58 (26.2) |
| Dust mite allergen, μg/g (tertiles of detectable levels) | |||
| <0.0523 (non-detectable) | 192 (44.4) | 192 (44.4) | 124 (46.1) |
| >=0.0523 <0.685 | 80 (18.5) | 80 (18.5) | 49 (18.2) |
| >=0.685 <2.725 | 80 (19) | 80 (19) | 44 (16.4) |
| >=2.725 | 80 (19) | 80 (19) | 52 (19.3) |
P <0.05 for comparison with children at baseline.
Numbers and percentages reflect missing information on some variables.
Table 2 summarizes the main results of the analysis of the relation between mode of delivery and allergic rhinitis at age 9 years. In bivariate analyses, cesarean section, a birth weight in the highest quartile (3.8 to 4.9 kg), and recurrent nasal catarrh in the first year of life were all associated with increased odds of allergic rhinitis at age 9 years. In contrast, exposure to an endotoxin level above the lowest quartile at age 2 to 3 months was associated with reduced odds of allergic rhinitis at age 9 years. After adjustment for relevant covariates, there was slight attenuation of the magnitude and statistical significance of the association between cesarean section and increased odds of allergic rhinitis. In this multivariate analysis, recurrent nasal catarrh in the first year of life and birth weight in the highest quartile were significantly associated with increased odds and endotoxin exposure in early life was associated with decreased odds of allergic rhinitis at age 9 years.
Table 2.
Analysis of the Relation Between Birth by Cesarean Section and Allergic Rhinitis at Age 9 Years
| Allergic Rhinitis |
||||
|---|---|---|---|---|
|
| ||||
| Variables | Yes | No | Odds ratio (95% confidence interval), P-value | |
| Unadjusted | Adjusted1 | |||
|
| ||||
| Mode of delivery | ||||
| Vaginal | 53 | 277 | 1 | 1 |
| Cesarean section | 27 | 75 | 1.9 (1.1–3.2), 0.02 | 1.8 (1.0–3.1), 0.047 |
| Quartiles of birth weight | ||||
| 1st | 15 | 91 | 1 | 1 |
| 2nd | 21 | 87 | 1.5 (0.7–3.0), 0.3 | 1.7 (0.8–3.5), 0.2 |
| 3rd | 17 | 91 | 1.1 (0.5–2.4), 0.7 | 1.3 (0.6–2.8), 0.5 |
| 4th | 27 | 82 | 2.0 (1.0–4.0), 0.05 | 2.0 (1.0–4.1), 0.05 |
| Endotoxin levels2 | ||||
| 1st quartile | 22 | 62 | 1 | 1 |
| 2nd to 4th quartiles | 43 | 222 | 0.6 (0.3–1.0), 0.04 | 0.5 (0.3–0.9), 0.03 |
| >=3 episodes of nasal catarrh in the first year of life | ||||
| No | 7 | 60 | 1 | 1 |
| Yes | 73 | 292 | 2.1 (0.9–4.9), 0.06 | 2.4 (1.0–5.6), 0.04 |
| Day care attendance In the first year of life | ||||
| No | 48 | 181 | 1 | 1 |
| Yes | 32 | 171 | 0.7 (0.4–1.2), 0.17 | 0.6 (0.4–1.1), 0.08 |
Adjusted for age and sex, in addition to all of the variables listed in the column.
Of the 432 participating children, 349 had data on indoor endotoxin levels at age 2–3 months.
Table 3 shows the results of the bivariate and multivariate analyses of the relation between birth by cesarean section and atopy at school age. In both bivariate and multivariate analyses, cesarean section was significantly associated with a twofold increase in the odds of atopy at school age. In the multivariate analysis, early exposure to endotoxin levels above the lowest quartile and physician-diagnosed croup in the first year of life were each associated with reduced odds of atopy at school age.
Table 3.
Analysis of the Relation Between Mode of Delivery and Atopy at School Age
| Atopy | ||||
|---|---|---|---|---|
|
| ||||
| Variables | Yes | No | Odds ratio (95% confidence interval), p value | |
| Unadjusted | Multivariate 1 | |||
|
| ||||
| Mode of delivery | ||||
| Vaginal | 105 | 101 | 1 | 1 |
| Cesarean section | 44 | 21 | 2.0(1.1–3.6), 0.02 | 2.1(1.1–3.9),0.02 |
| Endotoxin levels | ||||
| 1st quartile | 34 | 16 | 1 | 1 |
| 2nd to 4th quartile | 90 | 81 | 0.5(0.3–1.0),0.04 | 0.5(0.2–0.9),0.03 |
| Croup | ||||
| No | 140 | 101 | 1 | 1 |
| Yes | 9 | 21 | 0.3(0.1–0.7),0.004 | 0.3(0.1–0.6),0.003 |
Adjusted for mode of delivery, sex, household income, endotoxin level and croup.
Of the 271 children who had an assessment of allergic sensitization, 221 had data on indoor endotoxin levels at age 2 to 3 months.
Although we had limited statistical power to conduct a stratified analysis, we also examined whether the observed association between cesarean delivery and atopy differed by type of sensitization (to perennial vs. seasonal allergens). In a bivariate analysis, there were similar non-statistically significant trends for an association between cesarean section and either sensitization to at least one perennial allergen (OR=1.7, 95% CI=1.0–2.9, P=0.07) or sensitization to at least one seasonal allergen (OR=1.5, 95% CI=0.8–2.6, P=0.18).
We found no significant association between cesarean section and asthma in bivariate or multivariate analyses (Table 4). In addition, we found no association between birth by cesarean section and a major asthma symptom (wheeze) from ages 1 to 9 years (unadjusted hazard ratio=1.0, 95% CI=0.997–1.007, P=0.50).
Table 4.
Analysis of the Relation Between Mode of Delivery and Asthma at Age 9 Years
| Asthma | ||||
|---|---|---|---|---|
|
| ||||
| Variables | Yes | No | Odds ratio (95% confidence interval), p value | |
| Unadjusted | Multivariate 1 | |||
|
| ||||
| Mode of delivery | ||||
| Vaginal | 35 | 295 | 1 | |
| Cesarean section | 12 | 90 | 1.1 (0.6–2.3), 0.7 | |
| Bronchiolitis in the 1st year of life | ||||
| No | 37 | 343 | 1 | 1 |
| Yes | 10 | 42 | 2.2(1.0–4.8),0.04 | 2.3(1.0–5.2),0.04 |
| Highest tertile of dust mite allergen levels (>=2.73 ug/g) | ||||
| No | 33 | 319 | 1 | 1 |
| Yes | 14 | 66 | 2.1(1.0–4.0),0.04 | 2.2(1.1–4.5),0.03 |
| Current maternal asthma | ||||
| No | 28 | 279 | 1 | |
| Yes | 18 | 106 | 2.3(1.0–5.2).0.05 | 2.1(0.8–5.0),0.1 |
Adjusted for sex, household income, bronchiolitis, highest tertile of bedroom dust mite levels, and current maternal asthma.
With the exception of birth weight (see Table 2), there was no significant association between other prenatal and perinatal exposures (e.g., gestational age, breastfeeding) and any of the outcomes of interest.
DISCUSSION
To our knowledge, this is the first prospective birth cohort study of the relation between birth by cesarean section and atopy and allergic diseases at school age among children at high risk for atopy. In our study, birth by cesarean section was associated with increased risks of allergic rhinitis and atopy but not with asthma.
Table 5 summarizes the results of 12 previous epidemiologic studies of birth by cesarean section and atopy and/or atopic diseases, all of which were conducted among subjects not selected on the basis of a familial or parental history of atopy. Of these twelve studies, seven were retrospective and/or assessed mode of delivery and other covariates using data from existing databases 7,8,10,12,13,15,16, nine had limited 10,11,13,15,16,17,33 and/or variable 8,10,15,16 duration of follow-up during childhood, six reported losing >=20% of study participants at entry or during follow-up 8,9,13,17,14,33, and only five assessed allergic sensitization by objective methods 7,9,14,11,33. Thus, the seemingly conflicting findings of these studies can be due to selection bias due to differential loss of follow-up in some studies and to differences in: design (e.g., retrospective vs. prospective), characteristics of the populations studied (e.g., adults vs. children), sample size and statistical power, duration of follow-up, and definition of the outcomes of interest.
Table 5.
Summary of the Results of Previous Studies of Birth by Cesarean Section and Atopy or Atopic Diseases
| Reference (Number) | Study Design | Duration of Follow-up(f/u) | Sample size at f/u baseline | Odds ratio (95% CI) for the association between cesarean delivery and | ||
|---|---|---|---|---|---|---|
|
| ||||||
| Asthma | Hay fever or allergic rhinitis | Sensitization to ≥1 allergens | ||||
| Kero et al (7) | Retrospective/Database (DB) | 7 yrs | 59,927 | 1.2 (1.1–1.4) | N/A | 1.3 (0.7–2.7)* |
| Salam et al (8) | Retrospective | 8 to 17 yrs | 2,928/6,259 | 1.3 (1.0–1.8) | 1.6 (1.2–2.0) | N/A |
| McKeever et al (15) | Retrospective/DB | 0 to 11 yrs | 24,690/29,238 | 1.1 (1.0–1.1) | 1.0 (0.9–1.2) | N/A |
| Xu et al (9) | Prospective& | 31 yrs | 1,953/11,635 | 3.2 (1.5–6.8) | 1.3 (0.7–2.2) | 1.0 (0.6–1.6) |
| Nafstad et al (17) | Prospective | 4 yrs | 2,531/3,754 | 1.1 (0.7–1.8) | 1.2 (0.7–2.1) | N/A |
| Annesi-Maesano et al+ (16) | Retrospective | 1 to 18 yrs | 4,065/4,153 | 1.2 (0.7–2.0) | N/A | N/A |
| Maitra et al^ (14) | Prospective | 7 yrs | 7,495/14,062 | 1.2 (0.9–1.5) | N/A | 1.1 (0.9–1.5) |
| Renz-Polster et al (10) | Retrospective/DB | 3–10 yrs | 7,872/8,953 | 1.2 (1.0–1.5) | 1.4 (1.1–1.6) | N/A |
| Negele K et al (11) | Prospective | 2 yrs | 2,500/3,097 | N/A | 1.4 (0.8–2.4) | 1.7 (1.0–2.9) |
| Bager et al (12) | Retrospective/DB | 20–28 yrs | 9,722/10,482 | 1.3 (1.0–1.7) | 1.2 (0.9–1.5) | N/A |
| Eggesbo et al (33) | Prospective | 2 yrs | 2,803/3,621 | N/A | N/A | 3.2 (1.4–7.3). |
| Hakansson et al (13) | Retrospective case-control/DB | 1 yr | 650,959/916,131 | 1.1 (1.1–1.2)*** | N/A | N/A |
Of the 59,927 members of the birth registry, 131 underwent allergy skin testing
1,953 of 11,635 subjects in the birth cohort were included in the study. Obstetric data was obtained in all non-normal births but in only 10% of reportedly normal births.
Only emergency cesarean sections were included.
5,916 of the 14,062 participants underwent allergy skin testing.
Asthma was defined as at least one hospitalization for asthma.
N/A=Not available.
Seven studies 8,10,15,9,17,11,12 have examined birth by cesarean section and allergic rhinitis among subjects not selected on the basis of familial history of atopy (see Table 5). Of the five studies that found no association between cesarean section and allergic rhinitis among unselected subjects, three included children younger than 5 years of age (in whom a diagnosis of allergic rhinitis may be difficult) 15,17,11, two included adults ages 20 to 31 years 9,12, and three included data from fewer than 81% of eligible participants in their data analysis 9,17,11. Our finding of an increased risk of allergic rhinitis among children with parental history of atopy is consistent with the results of two studies of children not selected on the basis of parental history 8,10.
Five studies have examined birth by cesarean section and atopy (defined as sensitization to at least one allergen, as assessed by skin prick testing or IgE measurements) among children not selected on the basis of familial history (see Table 5)7,9,11,14,33. Limitations of the three studies that found no association between cesarean delivery and atopy include limited statistical power due to small sample size 7, potential selection bias 9,14, and small number of inhalant allergens tested 9. Two studies of children followed only to the age of 2 years reported a positive association between cesarean delivery and sensitization to at least one aero-allergen 11,33. Eggesbø et al. reported that cesarean delivery was associated with a threefold increase in the odds of parental report of food allergy (to egg, fish, or nuts) among 2,803 Norwegian children followed to age 2 years (95% CI for OR=1.4–7.3)33. Of relevance to our findings, the observed association between cesarean delivery and food allergy among Norwegian infants became much stronger after the analysis was stratified by maternal history of allergy. Norwegian children who were born by cesarean section and had a maternal history of allergy had nine-fold higher odds of food allergy than those who were born by vaginal delivery and had no maternal history of allergy (95% CI for OR=3.1–28). Similar results were reported for birth by cesarean section and allergy or intolerance to cow milk at age 2 years in a subsequent study of this Norwegian cohort 34.
Although seven of ten previous studies in children not selected on the basis of familial history showed that birth by cesarean section was significantly associated with increased odds of asthma in childhood or adulthood 7,8,9,10,12,13, five of these studies estimated only a modest increase in the odds of asthma due to cesarean delivery (OR ranging from 1.1 to 1.3, reviewed in a recent meta-analysis35). Thus, our negative finding may be due to limited statistical power to detect a weak association between cesarean delivery and asthma. However, we did not detect an association between birth by cesarean section and a major asthma symptom (wheeze) in our longitudinal analyses, for which we had adequate statistical power.
Children born by cesarean section are not exposed to the maternal vaginal and/or gut flora, which party explains changes in the neonatal microbial flora by mode of delivery4,5. Although results from cross-sectional 36–39 and birth cohort studies6,40, and findings from small clinical trials of probiotics 41–43 suggest that the composition of the neonatal gut flora influences the development of atopy and/or atopic diseases in childhood, this remains controversial 5. A longitudinal study of 957 Dutch infants showed that the presence of Clostridium difficile in stool samples at age 1 month (assessed by quantitative real-time PCR) was associated with increased risk of atopic dermatitis, recurrent wheeze, and allergic sensitization at age 2 years 6. In that study, early colonization with Escherichia coli was associated with parental report of eczema but not with objectively diagnosed atopic dermatitis. In contrast to those findings, a smaller study of European infants (n=324) followed from birth to age 18 months reported that neither time to gut colonization with 11 bacterial groups nor ratio of strict anaerobic to facultative anaerobic bacteria in cultures from neonatal stool samples was associated with eczema or food allergy 5. We have no neonatal stool cultures and thus cannot assess whether the observed association between cesarean delivery and atopy is due to differences in the neonatal gut flora of study participants by mode of delivery.
We previously reported preliminary findings of an association between cesarean delivery and increased levels of interleukin (IL-) 13 and interferon gamma in cord blood 44, which have in turn been associated with an increased risk for the development of atopy or asthma in childhood 45–48. Thus, cesarean delivery may affect early neonatal immune responses by mechanisms other than alteration of the neonatal gut flora. Such mechanisms may include reduced or absent labor in children born by cesarean section and non-passage through the birth canal during birth. Labor has been associated with alteration of neonatal immune responses (e.g., reduced lymphocytes and CD4+ helper T cells, and increased IL-6)49,50. In rodents, oral exposure to lipopolysaccharide during vaginal birth triggers activation of gut epithelial cells 51. In contrast, activation of the gut epithelia is not found in mice born by cesarean section.
Our finding of an inverse association between each of two early-life exposures (indoor endotoxin levels at age 2–3 months and physician-diagnosed croup in the first year of life) and allergic rhinitis at age 9 years confirm and extend our previous findings in this cohort at age 7 years 25,26.
Our study has two limitations in addition to those discussed above. First, allergy skin testing or measurement of IgE to common allergens could only be performed in a subgroup of study participants. Although there could be imbalances in the distribution of potential unmeasured confounders between children who did and did not undergo allergy skin testing or IgE measurements, selection bias is unlikely to be the main explanation for our results because there was no significant difference in the proportion of children born by cesarean section between children who did and did not undergo an assessment of allergic sensitization. In addition, our findings for atopy were consistent with those for allergic rhinitis, which were based on data for ~87% of children at baseline. Secondly, we could not separately examine the effects of scheduled and unscheduled cesarean deliveries because of limited statistical power.
In summary, our findings suggest that birth by cesarean section leads to an increased risk of allergic rhinitis and atopy among children at high risk for the development of atopy in childhood.
Acknowledgments
This study was supported by Grant AI/EHS35786 from the National Institutes of Health to Dr. Gold. Dr. Celedón is supported by grants HL66289, HL079966, and HL073373 from the National Institutes of Health.
We would like to give special thanks to the families participating in the Epidemiology of Home Allergens and Asthma Study.
Abbreviations
- AR
Allergic rhinitis
- CI
Confidence interval
- OR
Odds ratio
- IL
Interleukin
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