Editors’ choice articles
Birth by cesarean section, allergic rhinitis, and allergic
sensitization among children with a parental history of
Michael Pistiner, MD,a,b,dDiane R. Gold, MD, MPH,b,eHassen Abdulkerim, MS,bElaine Hoffman, PhD,fand
Juan C. Celedo ´n, MD, DrPHb,c,e
Background: Cesarean delivery can 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
Objective: We sought 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 a 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 was
defined 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 or more positive
skin test response 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 2-fold higher odds of atopy than those born
by vaginal delivery (odds ratio, 2.1; 95% CI, 1.1-3.9). In
multivariate analyses birth by cesarean section was significantly
associated with increased odds of allergic rhinitis (odds ratio,
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
a 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.
(J Allergy Clin Immunol 2008;122:274-9.)
Key words: Cesarean delivery, allergic rhinitis, atopy, childhood
Atopic diseases, such as atopic asthma, allergic rhinitis, and
eczema, are a major public health problem worldwide.1Perinatal
exposures might have a role in the pathogenesis of atopic dis-
eases, such as asthma and allergic rhinitis, which often begin in
delivery increased from 23% in 1990 to 28% in 2003.3Compared
with vaginal delivery, birth by cesarean section leads to long-last-
atopy, birth by cesarean section has been associated with an in-
creased risk of asthma, atopic diseases, or both in some stud-
ies7-13but not in others.14-17
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
a parental history of atopy followed from birth to age 9 years.
Subject recruitment for the Epidemiology of Home Allergens and
Asthma Study has been previously described in detail.18In brief, subjects
were recruited between September 1994 and August 1996. Eligibility crite-
ria included living inside route 128 (which encircles the Boston Metropoli-
tan Area), maternal age of 18 years or older, 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, hospital-
ization in the neonatal intensive care unit, or the presence of a congenital
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)19was administered by trained research assis-
tants to the child’s primarycaregiver untilthe ageof 2 years.Afterward,inter-
views 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.
Fromathe Division of Immunology, Children’s Hospital Boston;bthe Channing Labora-
Women’s Hospital; the Departments ofdPediatrics andeMedicine, Harvard Medical
School; andfthe Department of Biostatistics, Harvard School of Public Health.
Supported by grant AI/EHS35786 from the National Institutes of Health to Dr Gold.
Dr Celedo ´n is supported by grants HL66289, HL079966, and HL073373 from the
National Institutes of Health.
the NationalInstitutes of Health (NIH). D. R.Gold hasbeen a guestspeakerfor Indoor
Biotechnologies and has received research support from NIH and the UN Environ-
mental Protection Agency. J. C. Celedo ´n has received research support from NIH. The
rest of the authors have declared that they have no conflict of interest.
Received for publication December 26, 2007; revised May 8, 2008; accepted for publi-
cation May 9, 2008.
Available online June 24, 2008.
Reprint requests: Juan C. Celedo ´n, MD, DrPH, Channing Laboratory, 181 Longwood
Ave, Boston, MA 02115. E-mail: firstname.lastname@example.org.
? 2008 American Academy of Allergy, Asthma & Immunology
cthe Division of Pulmonary and Critical Care Medicine, Brigham and
OR: Odds ratio
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
for 21% of the participating children and were thus not included in the
Definition of other variables
Additional variables considered for inclusion in the multivariate analysis
included sex, annual household income,21child’s ethnicity,21number of older
siblings, maternal age at delivery, gestational age,20maternal asthma (ever
and current), paternal asthma (ever and current), in utero smoke exposure, av-
erage number of cigarettes smoked by adults in the household per day, breast-
feeding,22day care attendance in the first year of life,23antibiotic use in the
first year of life,24bottle feeding in the crib or bed before sleep,22physician-
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,25and levels of dust mite allergen
and endotoxin in house dust at age 2 to 3 months.26The methods used to col-
lect 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
Assessment of allergic sensitization
At a mean age of 7.4 years (range, 6.5-10.1 years), allergy skin testing was
performed in 248 children, and IgEs specific to common allergens were
volar aspect of the lower arms by using extracts for cat dander, dog dander,
mouse epithelia, cockroach (Blatella germanica), dust mite (Dermatopha-
goides pteronyssinus and Dermatophagoides farinae), ragweed, mixed trees,
mixed grasses, and molds (Alternaria, Aspergillus, Cladosporium, and Peni-
cillium species; Hollister-Stier Labs, Spokane, Wash). Histamine was used
as a positive control, and glycerinated saline was used as a negative control.
Skin test results were read as positive if the mean diameter of the wheal was
3 mm or larger after subtraction of the saline control wheal.
UniCAP 250 (Pharmacia & Upjohn, Kalamazoo, Mich) was used to assay
testing. IgE values to specific allergens were considered positive at 0.35 IU/
mL or greater.
Definition of outcomes
At age 9 years, asthma was defined as physician-diagnosed asthma and at
least 1 episode of wheezing in the previous year, and allergic rhinitis was
defined as physician-diagnosed allergic rhinitis and a history of nasal
discharge or sneezing apart from colds in the previous year.
Atopy (sensitization to ?1 allergens) was primarily defined as at least
1 positiveskin testresultorspecificIgE to the testedallergens at schoolage.26
to 1 or more perennial allergens and sensitization to 1 or more seasonal aller-
gens) and considered the degree of atopy (different categories for the number
of positiveskin tests or specific IgEs [eg, 0, 1-2, or ?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 and 108 months if the
child’s caretaker reported ‘‘wheezing or whistling in the chest’’ since the
Bivariate analyses were performedby using x2or Fisherexact testsfor cat-
egorical variables and 2-sided t tests or Wilcoxon tests for pairs of categorical
and continuous variables, as appropriate. Stepwise logistic regression was
est (asthma, allergic rhinitis, and atopy) while adjusting for potential con-
founders. The final models included variables that were significant at a P
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
same child handled by using the method of Andersen and Gill30and adjust-
described by Therneau and Grambsch.31To examine age-dependent associa-
tions, we calculated interaction terms between the age of the children at each
survey and the variables in the model.
The characteristics of the 498 study subjects have been
described in detail elsewhere.24,32Of the 498 participating chil-
dren, 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 nonwhite
ethnicity,to livein households with an annual income of less than
assessment of allergic sensitization or who were followed up to
age 9 years (Table I).
Therewere 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
up to age 9 years.
Table II summarizes the main results of the analysis of the re-
lation between mode of delivery and allergic rhinitis at age 9
years. In bivariate analyses cesarean section, a birth weight in
the highest quartile (3.8-4.9 kg), and recurrent nasal catarrh in
the first year of life were all associated with increased odds of al-
lergicrhinitis at age9 years. Incontrast, exposureto anendotoxin
level greater than the lowest quartile at age 2 to 3 months was as-
adjustment for relevant covariates, there was slight attenuation of
the magnitude and statistical significance of the association be-
tween 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 signifi-
cantly associated with increased odds and endotoxin exposure
at age 9 years.
Table III shows the results of the bivariate and multivariate
analyses of the relation between birth by cesarean section and at-
opy at school age. In both bivariate and multivariate analyses, ce-
sarean section was significantly associated with a 2-fold increase
in the odds of atopy at school age. In the multivariate analysis
tile and physician-diagnosed croup in the first year of life were
each associated with reduced odds of atopy at school age.
J ALLERGY CLIN IMMUNOL
VOLUME 122, NUMBER 2
PISTINER ET AL 275
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 1 perennial allergen (OR, 1.7; 95% CI,
1.0-2.9; P 5 .07) or sensitization to at least 1 seasonal allergen
(OR, 1.5; 95% CI, 0.8-2.6; P 5.18).
We found no significant association between cesarean section
and asthma in bivariate or multivariate analyses (Table IV). In
addition, we found no association between birth by cesarean sec-
(unadjusted hazard ratio, 1.0; 95% CI, 0.997-1.007; P 5.50).
With the exception of birth weight (see Table II), there was no
significantassociation between other prenatal and perinatalexpo-
sures (eg, gestational age and breast-feeding) and any of the out-
comes of interest.
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 V7-17,33summarizes the results of 12 previous epidemi-
ologic studies of birth by cesarean section and atopy, atopic dis-
eases, or both, all of which were conducted among subjects not
selected on the basis of a familial or parental history of atopy.
Of these 12 studies, 7 were retrospective, assessed mode of deliv-
ery and other covariates using data from existing databases, or
both7,8,10,12,13,15,16; 9 had limited,10,11,13,15-17,33variable,8,10,15,16
or both duration of follow-up during childhood; 6 reported losing
20% or more of the study participants at entry or during follow-
up8,9,13,14,17,33; and only 5 assessed allergic sensitization by
means of objective methods.7,9,11,14,33Thus the seemingly con-
flicting findings of these studies can be due to selection bias
TABLE I. Characteristics of participating children
(n 5 498), no. (%)
At 9 y follow-up*
(n 5 432), no. (%)
Children with assessment of allergen
sensitization* (n 5 271), no. (%)
Household income <$30,000
Asian and ‘‘other’’
Quartiles of birth weight (kg)
1.84 to <3.18
3.18 to <3.46
3.46 to <3.79
3.79 to <4.91
Season of birth
Gestational age <38.5 wk
Maternal history of asthma
No. of siblings in the child’s home
?3 Episodes of nasal catarrh in the first year of life
Physician-diagnosed bronchiolitis in the first year of life
Physician-diagnosed croup in the first year of life
Quartiles of endotoxin (EU/mg)
Dust mite allergen (mg/g; tertiles of detectable levels)
?0.0523 to <0.685
?0.685 to <2.725
*Numbers and percentages reflect missing information on some variables.
?P < .05 for comparison with children at baseline.
J ALLERGY CLIN IMMUNOL
276 PISTINER ET AL
ferences in design (eg, retrospective vs prospective), characteris-
and statistical power, duration of follow-up, and definition of the
outcomes of interest.
Seven studies8-12,15,17have examined birth by cesarean section
and allergic rhinitis among subjects not selected on the basis of
familialhistory ofatopy(see Table V). Ofthe 5studiesthat found
no association between cesarean section and allergic rhinitis
among unselected subjects, 3 included children younger than 5
years of age (in whom a diagnosis of allergic rhinitis might be
difficult),11,15,172 included adults ages 20 to 31 years,9,12and 3
data analysis.9,11,17Our finding of an increased risk of allergic
rhinitis among children with a parental history of atopy is consis-
tent with the results of 2 studies of children not selected on the
basis of a parental history.8,10
(defined as sensitization to at least 1 allergen, as assessed by skin
prick testing or IgE measurements) among children not selected
on the basis of familial history (see Table V).7,9,11,14,33Limita-
tions of the 3 studies that found no association between cesarean
delivery and atopy include limited statistical power because of
small sample size,7potential selection bias,9,14and small number
of inhalant allergens tested.9Two studies of children followed
only to the age of 2 years reported a positive association between
cesarean delivery and sensitization to at least 1 aeroallergen.11,33
Eggesbo et al33reported that cesarean delivery was associated
the observed association between cesarean delivery and food al-
lergy 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
whowere bornbyvaginal deliveryand had nomaternal history of
allergy(95% CIfor OR,3.1-28).Similar resultswerereportedfor
birth by cesarean section and allergy or intolerance to cow’s milk
at age 2 years in a subsequent study of this Norwegian cohort.34
significantly associated with increased odds of asthma in child-
hood or adulthood,7-10,12,135 of these studies estimated only a
(OR range, 1.1-1.3; reviewed in a recent meta-analysis35). Thus
tect a weak association between cesarean delivery and asthma.
dinal analyses, for which we had adequate statistical power.
TABLE II. Analysis of the relation between birth by cesarean
section and allergic rhinitis at age 9 years
rhinitisOR (95% CI), P value
VariablesYes No UnadjustedAdjusted*
Mode of delivery
Quartiles of birth weight
?3 Episodes of nasal
catarrh in the first
year of life
Day care attendance
in the first year of life
53 277 1
75 1.9 (1.1-3.2), .02 1.8 (1.0-3.1), .047
87 1.5 (0.7-3.0), .3
91 1.1 (0.5-2.4), .7
82 2.0 (1.0-4.0), .05 2.0 (1.0-4.1), .05
1.7 (0.8-3.5), .2
1.3 (0.6-2.8), .5
43 222 0.6 (0.3-1.0), .04 0.5 (0.3-0.9), .03
7 60 11
73 292 2.1 (0.9-4.9), .06 2.4 (1.0-5.6), .04
48 181 1
32 171 0.7 (0.4-1.2), .17 0.6 (0.4-1.1), .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 to
TABLE III. Analysis of the relation between mode of delivery and
atopy at school age
AtopyOR (95% CI), P value
Mode of delivery
2.0 (1.1-3.6), .02
2.1 (1.1-3.9), .02
0.5 (0.3-1.0), .04
0.5 (0.2-0.9), .03
0.3 (0.1-0.7), .004
0.3 (0.1-0.6), .0039
*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.
TABLE IV. Analysis of the relation between mode of delivery and
asthma at age 9 years
AsthmaOR (95% CI), P value
Mode of delivery
Bronchiolitis in the
first year of life
of dust mite
1.1 (0.6-2.3), .7
2.2 (1.0-4.8), .04
2.3 (1.0-5.2), .04
2.1 (1.0-4.0), .04
2.2 (1.1-4.5), .03
2.3 (1.0-5.2), .052.1 (0.8-5.0), .1
*Adjusted for sex, household income, bronchiolitis, highest tertile of bedroom dust
mite levels, and current maternal asthma.
J ALLERGY CLIN IMMUNOL
VOLUME 122, NUMBER 2
PISTINER ET AL 277
Children born by cesarean section are not exposed to the
maternal vaginal flora, gut flora, or both, which party explains
though results from cross-sectional36-39and birth cohort stud-
ies6,40and findings from small clinical trials of probiotics41-43
suggest that the composition of the neonatal gut flora influences
the development of atopy, atopic diseases, or both in childhood,
this remains controversial.5Alongitudinalstudy of 957 Dutchin-
fants showed that the presence of Clostridium difficile in stool
samples at age 1 month (assessed by means of quantitative real-
study early colonization with Escherichia coli was associated
with parental report of eczema butnotwith objectivelydiagnosed
atopic dermatitis. In contrast to those findings, a smaller study of
European infants (n 5 324) 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 bacte-
ria in cultures from neonatal stool samples was associated with
eczema or food allergy.5We 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 IL-13 and
IFN-g in cord blood,44which have in turn been associated with
an increased risk for the development of atopy or asthma in
childhood.45-48Thus cesarean delivery might affect early neona-
tal immune responses through mechanisms other than alteration
of the neonatal gut flora. Such mechanisms can include reduced
or absent labor in children born by cesarean section and nonpas-
sage through the birth canal during birth. Labor has been asso-
ciated with alteration of neonatal immune responses (eg,
reduced lymphocytes and CD41THcells and increased IL-6
levels).49,50In rodents oral exposure to LPS during vaginal birth
triggers activation of gut epithelial cells.51In contrast, activation
of the gut epithelia is not found in mice born by cesarean
Our findings of an inverse association between each of 2 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 2 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 chil-
dren who did and did not undergo allergy skin testing or IgE
measurements, selection bias is unlikely to be the main explana-
tion for our results because there was no significant difference in
the proportion of children born by cesarean section between the
groups of 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 approximately 87% of children at baseline. Second, we
could not separately examine the effects of scheduled and
unscheduled cesarean deliveries because of limited statistical
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 of atopy in childhood.
and Asthma Study.
should be considered as a potential risk of cesarean delivery
among children with a parental history of atopy.
TABLE V. Summary of the results of previous studies of birth by cesarean section and atopy or atopic diseases
OR (95% CI) for association
between cesarean delivery and:
Sample size at
Hay fever or
to $1 allergen
Kero et al7
Salam et al8
McKeever et al15
Xu et al9
Nafstad et al17
Annesi-Maesano et al16?
Maitra et al14§
Renz-Polster et al10
Negele et al11
Bager et al12
Eggesbo et al33
Hakansson and Kallen13
NA 1.3 (0.7-2.7)*
DB, Database; NA, not available.
*Of the 59,927 members of the birth registry, 131 underwent allergy skin testing.
?One thousand nine hundred fifty-three of 11,635 subjects in the birth cohort were included in the study. Obstetric data were obtained in all nonnormal births but in only 10% of
reportedly normal births.
?Only emergency cesarean sections were included.
§Five thousand nine hundred sixteen of 14,062 participants underwent allergy skin testing.
kAsthma was defined as at least 1 hospitalization for asthma.
J ALLERGY CLIN IMMUNOL
278 PISTINER ET AL
REFERENCES Download full-text
1. Asher MI, Montefort S, Bjorksten B, et al. Worldwide time trends in the prevalence
of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood:
ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet
2. Yunginger JW, Reed CE, O’Connell EJ, et al. A community-based study of the ep-
idemiology of asthma. Incidence rates, 1964-1983. Am Rev Respir Dis 1992;146:
3. Menacker F. Trends in cesarean rates for first births and repeat cesarean rates for
low-risk women: United States, 1990-2003. Natl Vital Stat Rep 2005;54:1-8.
4. Gronlund MM, Lehtonen OP, Eerola E, et al. Fecal microflora in healthy infants
born by different methods of delivery: permanent changes in intestinal flora after
cesarean delivery. J Pediatr Gastroenterol Nutr 1999;28:19-25.
5. Adlerberth I, Strachan DP, Matricardi PM, et al. Gut microbiota and development
of atopic eczema in 3 European birth cohorts. J Allergy Clin Immunol 2007;120:
6. Penders J, Thijs C, van den Brandt PA, et al. Gut microbiota composition and de-
velopment of atopic manifestations in infancy: the KOALA Birth Cohort Study.
7. Kero J, Gissler M, Gronlund MM, et al. Mode of delivery and asthma—is there a
connection? Pediatr Res 2002;52:6-11.
8. Salam MT, Margolis HG, McConnell R, et al. Mode of delivery is associated with
asthma and allergy occurrences in children. Ann Epidemiol 2006;16:341-6.
9. Xu B, Pekkanen J, Hartikainen AL, et al. Caesarean section and risk of asthma and
allergy in adulthood. J Allergy Clin Immunol 2001;107:732-3.
10. Renz-Polster H, David MR, Buist AS, et al. Caesarean section delivery and the risk
of allergic disorders in childhood. Clin Exp Allergy 2005;35:1466-72.
11. Negele K, Heinrich J, Borte M, et al. Mode of delivery and development of atopic
disease during the first 2 years of life. Pediatr Allergy Immunol 2004;15:48-54.
12. Bager P, Melbye M, Rostgaard K, et al. Mode of delivery and risk of allergic rhi-
nitis and asthma. J Allergy Clin Immunol 2003;111:51-6.
13. Hakansson S, Kallen K. Caesarean section increases the risk of hospital care in
childhood for asthma and gastroenteritis. Clin Exp Allergy 2003;33:757-64.
14. Maitra A, Sherriff A, Strachan D, et al. Mode of delivery is not associated with
asthma or atopy in childhood. Clin Exp Allergy 2004;34:1349-55.
15. McKeever TM, Lewis SA, Smith C, et al. Mode of delivery and risk of developing
allergic disease. J Allergy Clin Immunol 2002;109:800-2.
16. Annesi-Maesano I, Moreau D, Strachan D. In utero and perinatal complications
preceding asthma. Allergy 2001;56:491-7.
17. Nafstad P, Magnus P, Jaakkola JJ. Risk of childhood asthma and allergic rhinitis in
relation to pregnancy complications. J Allergy Clin Immunol 2000;106:867-73.
18. Gold DR, Burge HA, Carey V, et al. Predictors of repeated wheeze in the first year
of life: the relative roles of cockroach, birth weight, acute lower respiratory illness,
and maternal smoking. Am J Respir Crit Care Med 1999;160:227-36.
19. Ferris BG Jr. Epidemiology standardization project. Am Rev Respir Dis 1978;118:
20. Raby BA, Celedo ´n JC, Litonjua AA, et al. Low-normal gestational age as a predic-
tor of asthma at six years of age. Pediatrics 2004;114:e327-32.
21. Litonjua AA, Carey VJ, Burge HA, et al. Parental history and the risk for childhood
asthma. Does mother confer more risk than father? Am J Respir Crit Care Med
22. Celedo ´n JC, Litonjua AA, Ryan L, et al. Bottle feeding in the bed or crib before
sleep time in the first year of life and wheezing in the first five years of life. Pedi-
23. Celedo ´n JC, Wright RJ, Litonjua AA, et al. Day care attendance in early life, ma-
ternal history of asthma, and asthma at age 6 years. Am J Respir Crit Care Med
24. Celedo ´n JC, Litonjua AA, Ryan L, et al. Lack of association between antibiotic use
in the first year of life and asthma, allergic rhinitis, or eczema at age 5 years. Am
J Respir Crit Care Med 2002;166:72-5.
25. Ramsey CD, Gold DR, Litonjua AA, et al. Respiratory illnesses in early life and
asthma and atopy in childhood. J Allergy Clin Immunol 2007;119:150-6.
26. Celedon JC, Milton DK, Ramsey CD, et al. Exposure to dust mite allergen and en-
dotoxin in early life and asthma and atopy in childhood. J Allergy Clin Immunol
27. Luczynska CM, Arruda LK, Platts-Mills TA, et al. A two-site monoclonal antibody
ELISA for the quantification of the major Dermatophagoides spp. allergens, Der p
I and Der f I. J Immunol Methods 1989;118:227-35.
28. Milton DK, Feldman HA, Neuberg DS, et al. Environmental endotoxin measure-
ment: the Kinetic Limulus Assay with Resistant-parallel-line Estimation. Environ
29. Milton DK, Johnson DK, Park JH. Environmental endotoxin measurement: inter-
ference and sources of variation in the Limulus assay of house dust. Am Ind
Hyg Assoc J 1997;58:861-7.
30. Andersen PK, Gill RD. Cox’s regression model for counting processes: a large
sample study. Ann Stat 1982;10:1110-20.
31. Therneau TM, Grambsch J. Extending the Cox model. Modeling survival data.
New York: Springer-Verlag; 2000. p. 185-6.
32. Celedon JC, Litonjua AA, Weiss ST, et al. Day care attendance in the first year of
life and illnesses of the upper and lower respiratory tract in children with familial
history of atopy. Pediatrics 1999;104:495-500.
33. Eggesbo M, Botten G, Stigum H, et al. Is delivery by cesarean section a risk factor
for food allergy? J Allergy Clin Immunol 2003;112:420-6.
34. Eggesbo M, Botten G, Stigum H, et al. Cesarean delivery and cow milk allergy/in-
tolerance. Allergy 2005;60:1172-3.
35. Thavagnanam S, Fleming J, Bromley A, et al. A meta-analysis of the association
between Caesarean section and childhood asthma. Clin Exp Allergy 2008;38:
36. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering
Committee. Worldwide variation in prevalence of symptoms of asthma, allergic
rhinoconjunctivitis, and atopic eczema: ISAAC. Lancet 1998;351:1225-32.
37. Sepp E, Julge K, Vasar M, et al. Intestinal microflora of Estonian and Swedish in-
fants. Acta Paediatr 1997;86:956-61.
38. Bjorksten B, Naaber P, Sepp E, et al. The intestinal microflora in allergic Estonian
and Swedish 2-year-old children. Clin Exp Allergy 1999;29:342-6.
39. Bottcher MF, Nordin EK, Sandin A, et al. Microflora-associated characteristics in
faeces from allergic and nonallergic infants. Clin Exp Allergy 2000;30:1590-6.
40. Kalliomaki M, Kirjavainen P, Eerola E, et al. Distinct patterns of neonatal gut mi-
croflora in infants in whom atopy was and was not developing. J Allergy Clin Im-
41. Kalliomaki M, Salminen S, Poussa T, et al. Probiotics and prevention of atopic dis-
ease: 4-year follow-up of a randomised placebo-controlled trial. Lancet 2003;361:
42. Kalliomaki M, Salminen S, Arvilommi H, et al. Probiotics in primary prevention of
atopic disease: a randomised placebo-controlled trial. Lancet 2001;357:1076-9.
43. Weston S, Halbert AR, Richmond P, et al. Effects of probiotics on atopic dermati-
tis: a randomised controlled trial. Arch Dis Child 2005;90:892-7.
44. Ly NP, Ruiz-Perez B, Onderdonk AB, et al. Mode of delivery and cord blood cy-
tokines: a birth cohort study. Clin Mol Allergy 2006;4:13.
45. Lange J, Ngoumou G, Berkenheide S, et al. High interleukin-13 production by phy-
tohaemagglutinin- and Der p 1-stimulated cord blood mononuclear cells is associ-
ated with the subsequent development of atopic dermatitis at the age of 3 years.
Clin Exp Allergy 2003;33:1537-43.
46. Neaville WA, Tisler C, Bhattacharya A, et al. Developmental cytokine response
profiles and the clinical and immunologic expression of atopy during the first
year of life. J Allergy Clin Immunol 2003;112:740-6.
47. Rowe J, Heaton T, Kusel M, et al. High IFN-gamma production by CD81 T cells
and early sensitization among infants at high risk of atopy. J Allergy Clin Immunol
48. Sharp MJ, Rowe J, Kusel M, et al. Specific patterns of responsiveness to microbial
antigens staphylococcal enterotoxin B and purified protein derivative by cord blood
mononuclear cells are predictive of risk for development of atopic dermatitis. Clin
Exp Allergy 2003;33:435-41.
49. Pittard WB 3rd, Schleich DM, Geddes KM, et al. Newborn lymphocyte subpopu-
lations: the influence of labor. Am J Obstet Gynecol 1989;160:151-4.
50. Macaubas C, de Klerk NH, Holt BJ, et al. Association between antenatal cytokine
production and the development of atopy and asthma at age 6 years. Lancet 2003;
51. Lotz M, Gutle D, Walther S, et al. Postnatal acquisition of endotoxin tolerance in
intestinal epithelial cells. J Exp Med 2006;203:973-84.
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