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Early life risk factors for childhood asthma

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Early life risk factors for childhood asthma

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EARLY LIFE RISK FACTORS FOR CHILDHOOD ASTHMA

by

Md. Towhid Salam

A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(EPIDEMIOLOGY)

August 2009

Copyright 2009 Md. Towhid Salam

ii
Acknowledgements

I am indebted to Dr. Frank Gilliland for his guidance, support and encourgament in
conducting my research for this dissertation. Drs. Rob McConnell, Bryan Langholz,
Sue Ingles, and Louis Dubeau served on my guidance committee and I am thankful for
their efforts. I am also indebted to Drs. Yu-Fen Li, Helene Margolis, James McGregor
and Prof. Edward Avol for providing additional suggestions and comments in the
preparation of the manuscripts.

I am thankful to Drs. Stanley Azen and Wendy Mack for their efforts as graduate
advisors. Special thanks go to the members of the Children’s Health Study Team for
their excellent data management support.

Last but not the least, this work could not be accomplished without the support,
understanding and encouragement of my parents and my wife, Kohinoor. Our son
Tahrir and daughter Tanzeela let me work on the dissertation on many weekends and
evenings, and I appreciate their sacrifice.

iii
Table of Contents

Acknowledgements ........................................................................................................ii

List of Tables.................................................................................................................vi

Abstract........................................................................................................................viii

Chapter 1: Introduction...................................................................................................1
Chapter 1 References.................................................................................................4

Chapter 2: Definition, Classification and Pathophysiology of Childhood Asthma........5
2.1 Summary of Key Points.......................................................................................5
2.2 Asthma Definition ...............................................................................................6
2.3 Clinical Diagnosis of Asthma in Children...........................................................7
2.3.1 Role of Commonly Used Objective Tests in Asthma Diagnosis in
Children ............................................................................................................7
2.4 Classification of Childhood Asthma..................................................................10
2.4.1 Atopic and Non-atopic asthma ..............................................................11
2.5. Environmental Influences on Pulmonary and Immune Developments ............13
2.5.1 Environmental Influences on Lung Growth and Development .............13
2.5.2 Environmental Influences on Immune Development ............................16
2.6 Pathophysiology of Asthma...............................................................................25
2.6.1 Airway Inflammation.............................................................................25
2.6.2 Airway Remodeling...............................................................................27
2.6.3 Bronchial Hyperresponsiveness.............................................................28
Chapter 2 References...............................................................................................30

Chapter 3: Descriptive Epidemiology of Childhood Asthma.......................................44
3.1 Natural History of Childhood Asthma...............................................................44
3.1.1 Secular Trend in Childhood Asthma Incidence and Prevalence............44
3.1.2 Geographical Variation in Asthma Prevalence......................................45
3.1.3 Migration Studies...................................................................................48
3.1.4 Twin and Family-Based Studies............................................................50
3.1.5 Socioeconomic Status (SES) and Race..................................................51
3.1.6 Age of Onset and Age-Related Asthma Phenotypes .............................53
3.1.7 Gender....................................................................................................53
3.2 Determinants of Natural History of Childhood Asthma....................................55
3.3 Consequences of Childhood Asthma.................................................................56
3.4 Life Course Approach for Childhood Asthma...................................................58
Chapter 3 References...............................................................................................60

iv
Chapter 4: Exposures and Events during Pregnancy and Childbirth and Childhood
Asthma..........................................................................................................................73
4.1 Introduction........................................................................................................73
4.2 Preconception Factors........................................................................................75
4.2.1 Maternal asthma.....................................................................................76
4.2.2 Maternal age ..........................................................................................77
4.2.3 Maternal Endogenous Sex Steroid Hormones.......................................77
4.2.4 Maternal Use of Exogenous Sex Steroid Hormones .............................78
4.2.5 Parity (Birth Order/Sibship Size)...........................................................79
4.3 Exposures/Events In Utero ................................................................................80
4.3.1 Maternal Smoking during Pregnancy ....................................................80
4.3.2 Maternal Diet .........................................................................................88
4.3.3 Maternal Alcohol Consumption.............................................................90
4.3.4 Maternal Infections and Antibiotic Use.................................................91
4.3.5 Other Maternal Medication Use ............................................................92
4.3.6 Maternal Psychological Stress...............................................................94
4.3.7 Environmental Exposures......................................................................95
4.3.8 Other Pregnancy Related Factors ..........................................................99
4.4 Birth Outcomes................................................................................................101
4.4.1 Birth by Cesarean Section....................................................................101
4.4.2 Other Birth Related Factors .................................................................105
4.5 Summary and Conclusions ..............................................................................105
Chapter 4 References.............................................................................................109

Chapter 5: Maternal Fish Consumption during Pregnancy and Risk of Early
Childhood Asthma (Manuscript 1).............................................................................125
Chapter 5 Abstract .................................................................................................125
5.1 Introduction......................................................................................................126
5.2 Materials and Methods ....................................................................................128
5.2.1 Study Design and Subjects ..................................................................128
5.2.2 Exposure Assessment ..........................................................................129
5.2.3 Outcome Assessment...........................................................................130
5.2.4 Statistical Analysis...............................................................................131
5.3 Results..............................................................................................................132
5.4 Discussion........................................................................................................137
Chapter 5 References.............................................................................................142

Chapter 6: Mode of Delivery Is Associated With Asthma and Allergy
Occurrences in Children (Manuscript 2) ....................................................................145
Chapter 6 Abstract .................................................................................................145
6.1 Introduction......................................................................................................146
6.2 Methods ...........................................................................................................147
6.3 Results..............................................................................................................150

v
6.4 Discussion........................................................................................................154
Chapter 6 References.............................................................................................160

Chapter 7: Early-Life Environmental Risk Factors for Asthma: Findings from
the Children's Health Study (Manuscript 3) ...............................................................164
Chapter 7 Abstract .................................................................................................164
7.1 Introduction......................................................................................................165
7.2 Materials and Methods ....................................................................................166
7.2.1 Subject selection ..................................................................................166
7.2.2 Data collection .....................................................................................168
7.2.3 Exposure assessment............................................................................168
7.2.4 Outcome assessment............................................................................169
7.2.5 Assessment of confounders and effect modifiers ................................169
7.2.6 Statistical analysis................................................................................170
7.3 Results..............................................................................................................171
7.4 Discussion........................................................................................................180
Chapter 7 References.............................................................................................188

Chapter 8: Summary and Future Research Plans .......................................................192
8.1 Summary..........................................................................................................192
8.2 Future Research Plans......................................................................................195

Bibliography ...............................................................................................................200

vi
List of Tables

Table 2.1. Classification of bronchial hyperresponsiveness ..........................................9

Table 2.2. Prevalences of skin-prick test (SPT) positivity and doctor-diagnosed
asthma in selected populations. .............................................................................12

Table 2.3. Different stages of lung growth and development in pre- and
postnatal life...........................................................................................................13

Table 3.1. Major findings of some selected studies that examined the natural
history of childhood asthma...................................................................................46

Table 3.2. Trend in asthma prevalence in some developed countries ..........................47

Table 4.1. Maternal smoking during pregnancy and asthma in children:
Findings published during 1996-2006.* ................................................................83

Table 4.2. Cord blood IgE and asthma or wheeze occurrence in children...................97

Table 4.3. Review of papers that examined the association between Caesarean
section delivery and asthma.................................................................................103

Table 5.1. Selected characteristics of the case-control study participants..................133

Table 5.2. Associations between maternal oily-fish and fish-stick consumption
during pregnancy and child’s risk of any, early transient, early persistent
and late-onset asthma...........................................................................................134

Table 5.3. Joint effects of maternal asthma and maternal oily-fish consumption
during pregnancy on children’s asthma risk. .......................................................136

Table 6.1. Selected characteristics of the study participants from the Children’s
Health Study born at term in California between 1975 and 1987. ......................150

Table 6.2. Associations between mode of delivery and different respiratory and
allergic outcomes .................................................................................................152

Table 6.3. Mode of delivery on joint outcomes of asthma and allergy......................153

vii
Table 7.1. Selected characteristics of the counter-matched case-control study
participants selected from the Children’s Health Study. .....................................172

Table 7.2. Associations between early transient wheezing and any, early
persistent and late onset asthma and exposures to wood/oil smoke, soot or
exhaust, cockroach and pets.................................................................................174

Table 7.3. Associations between early transient wheezing and any, early
persistent and late onset asthma and exposures to herbicides and pesticides......175

Table 7.4. Associations between early transient wheezing and any, early
persistent and late onset asthma and exposures to farm animal and farm
crops or dust.........................................................................................................177

Table 7.5. Associations between early transient wheezing and any, early
persistent and late onset asthma and exposures to breastfeeding, number
of sibs and daycare attendance.............................................................................178

viii
Abstract

Asthma is the most common chronic inflammatory disease in childhood. The disease
often starts early in life with significant burden to children and their families and the
healthcare system. An accumulating body of evidence indicates that both prenatal and
early life exposures play uniquely important roles in asthma occurrence by modulating
airway and immune functions. In addition, timing of such exposures during these
periods is likely to modulate the growth and development of airways and immune
functions. Extensive literature reviews were done to critically evaluate earlier work
and to understand the mechanisms of the underlying associations. The findings of the
analyses are encouraging. Using data from the southern California Children’s Health
study, both prenatal and early life exposures were found to be associated with asthma
occurrence in children. Additionally, timing of exposure in infancy and family history
of asthma modified some of these associations. Some of the associations were stronger
for particular asthma phenotypes. Given the enormous burden from childhood asthma,
further research is needed to assess the role of these and other genetic, epigenetic and
environmental factors during critical windows of development across distinct asthma
phenotypes. These findings also indicate that any intervention strategy to reduce the
burden of asthma in young children should target prenatal and early life as a critical
time point to modulate exposures to prevent disease occurrence.

1
Chapter 1: Introduction

Childhood asthma is a major clinical and public health problem worldwide and the
prevalence of childhood asthma has been on the rise over several decades in developed
nations including the United States (US).
1-4
Between 1980 and 1999, asthma
prevalence increased 83% among children below 5 years in the US.
2
Although asthma
prevalence has reached a plateau in the United States in recent years, it still remains
the most common chronic disease in children affecting approximately 1 in 12
children.
5
The economic burden of childhood asthma on healthcare system is high. In
the US, it has been estimated that two billion dollars are spent annually on healthcare
costs for managing childhood asthma.
6

Asthma is a chronic inflammatory disorder of the airways that is characterized by
recurrent episodes of wheezing, shortness of breath, chest tightness, and coughing,
which disproportionately affects children.
5, 7
Asthma was not a common disease in the
1960s and even in the last decade the prevalence of asthma in underdeveloped
countries was much lower than that in the developed countries of North America,
western Europe, Australia and New Zealand.
4

Many changes that have occurred in the western countries since 1960 in both the
indoor and in the outdoor environment have been implicated in asthma pathogenesis.
For example, ventilation rate in houses has decreased and upholstered furniture use

2
has increased in western societies
8
that may have increased indoor temperature and
humidity resulting in growth of house dust mite in some regions. With greater
numbers of vehicles in recent decades, ambient air pollutant levels such as particulates
(e.g., PM
10
, PM
2.5
), ozone, and nitrogen oxide have increased in some regions even
though there has been significant effort to maintain good air quality. Over the last five
decades, lifestyle has also changed significantly in the western world. For example,
family size has become smaller, and people have changed their diet from a “traditional
diet” that contained more fruits, vegetables, lean meat and fish to a “western diet” that
contains more saturated and trans fatty acids and omega-6 polyunsaturated fatty acids
(n-6 PUFAs).
9

Although the etiologies of childhood asthma remain to be firmly established, a
growing body of evidence indicates that both in utero and early life experiences and
exposures are important in childhood asthma occurrence. Because asthma often
manifests in early childhood, these changed environmental and lifestyle factors may
influence early life pulmonary and immune development that may be associated with
asthma occurrence in early childhood.

For this dissertation, we examined the associations between various in utero and early
life exposures and early childhood asthma using the data from the Early Asthma Risk
factor Study (EARS) and the Children’s Health Study (CHS). The EARS is a counter-
matched nested case-control study conducted in children who participated in the

3
Children’s Health Study (CHS), a population based study that has been examining the
effect of different exposures on respiratory health among children living in 12
southern California communities.

The context for these studies was provided through a review of the definition,
classification, and pathophysiology of asthma (Chapter 2) and a presentation of the
descriptive epidemiology (Chapter 3) and prenatal and at birth risk factors for
childhood asthma (Chapter 4). In Chapter 5, we present our findings of the
associations between maternal intakes of fish during pregnancy and asthma occurrence
in children by age 5 years using the EARS data. The associations of mode of delivery
on asthma and other atopic disease outcomes in California-born CHS participants are
presented in Chapter 6 using data obtained in the CHS and from the birth certificates.
In Chapter 7, we have examined the impact of early life exposures (e.g., pesticide,
wood smoke, cockroach, breastfeeding, day care attendance) and parity on asthma
occurrence by age 5 years using the EARS data. Finally, we provided an overall
summary regarding the role of prenatal and early life exposures and events in asthma
development during childhood and proposed some areas for further research (Chapter
8).

4
Chapter 1 References
1. Mannino DM, Homa DM, Pertowski CA, et al. Surveillance for asthma--
United States, 1960-1995. MMWR CDC Surveill Summ 1998; 47:1-27.

2. Mannino DM, Homa DM, Akinbami LJ, Moorman JE, Gwynn C, Redd SC.
Surveillance for asthma--United States, 1980-1999. MMWR Surveill Summ
2002; 51:1-13.

3. Variations in the prevalence of respiratory symptoms, self-reported asthma
attacks, and use of asthma medication in the European Community Respiratory
Health Survey (ECRHS). Eur Respir J 1996; 9:687-95.

4. Worldwide variation in prevalence of symptoms of asthma, allergic
rhinoconjunctivitis, and atopic eczema: ISAAC. The International Study of
Asthma and Allergies in Childhood (ISAAC) Steering Committee. Lancet
1998; 351:1225-32.

5. Moorman JE, Rudd RA, Johnson CA, et al. National surveillance for asthma--
United States, 1980-2004. MMWR Surveill Summ 2007; 56:1-54.

6. Landrigan PJ, Schechter CB, Lipton JM, Fahs MC, Schwartz J. Environmental
pollutants and disease in American children: estimates of morbidity, mortality,
and costs for lead poisoning, asthma, cancer, and developmental disabilities.
Environ Health Perspect 2002; 110:721-8.

7. Gold DR, Wright R. Population disparities in asthma. Annu Rev Public Health
2005; 26:89-113.

8. Platts-Mills TA, Perzanowski M, Carter MC, Woodfolk JA. The rising
prevalence and severity of asthma in western society: are the causes of asthma
the causes of the increase? In: Platts-Mills TA, ed. Asthma: causes and
mechanisms of an epidemic inflammatory disease. London: Lewis Publishers,
1999:1-22.

9. Simopoulos AP. Omega-3 fatty acids in inflammation and autoimmune
diseases. J Am Coll Nutr 2002; 21:495-505.

5
Chapter 2: Definition, Classification and Pathophysiology of Childhood Asthma

2.1 Summary of Key Points
• Asthma is a multifactorial, heterogeneous disease of the lung characterized by
airway obstruction, bronchial hyperresponsiveness (BHR), chronic
inflammation, mucus hypersecretion, and reparative airway remodeling with
subepithelial fibrosis.
• Asthma often presents in early childhood and the highest prevalence is seen
among children.
• Most children with asthma present with the recurrent symptoms of shortness of
breath, wheezing, cough, and chest tightness.
• The diagnosis is often based on clinical presentations. Determination of airflow
obstruction by measuring FEV1 and reversibility of airflow obstruction
following β
2
-agonist can aid diagnosis in children over 5 years.
• Parental report of physician-diagnosed asthma has been well validated and
widely used in epidemiologic studies.
• Family history of asthma (representing genetic predisposition) has been
consistently associated with increased asthma risk.
• Because the disease often manifests in early childhood, environmental
exposures during prenatal and early life that modulate pulmonary and immune
functions could affect asthma risk.

6
2.2 Asthma Definition
According to the Global Initiative for asthma (GINA) and to the Expert Panel Report 2
(EPR-2) by the National Asthma Education and Prevention Program (NAEPP), the
working definition is that
Asthma is a chronic inflammatory disorder of the airways in which many cells
and cellular elements play a role, in particular, mast cells, eosinophils, T
lymphocytes, macrophages, neutrophils, and epithelial cells. In susceptible
individuals, this inflammation causes recurrent episodes of wheezing,
breathlessness, chest tightness, and coughing, particularly at night or in the
early morning. These episodes are usually associated with widespread but
variable airflow obstruction that is often reversible either spontaneously or
with treatment. The inflammation also causes an associated increase in the
existing BHR to a variety of stimuli.
1, 2

In addition, the NAEPP Expert Panel also recognizes that recurrent episodes of cough
and wheeze are almost always due to asthma in both children and adults and in some
cases cough could be the only symptom.”
2

From the above definition, it is clearly evident that asthma remains a clinical
syndrome diagnosed mainly on the basis of respiratory symptoms, physical
examination, and determining reversibility of airway obstruction. Questionnaire based
asthma definition has been used in many epidemiologic studies. There are validated
questionnaires for defining asthma for large epidemiologic studies.
3-5
These
questionnaires inquire about asthma symptoms such wheeze, cough, nocturnal cough,
and chest tightness or physician diagnosis of asthma.

7
2.3 Clinical Diagnosis of Asthma in Children
The NAEPP EPR-3
6
currently recommends that clinicians should diagnose asthma
based on:
Presence of episodic symptoms of wheeze, cough, shortness of breath, and chest
tightness
Determining reversible airflow obstruction (FEV
1
<80% predicted; FEV
1
/FVC
<65% or below the lower limit of normal), and
Exclusion of alternative diagnoses (e.g., vocal cord dysfunction, vascular rings,
foreign bodies, or other pulmonary diseases)

Additionally, the EPR-3 recommends additional testing in suspected asthma cases
when spirometry is normal, other coexisting disease conditions or contributing factors
are suspected. These tests include assessing diurnal variation in peak flow,
determination of bronchial hyperresponsiveness (BHR; tests commonly done with
methacholine, histamine, or exercise), chest X-ray, or determining allergic
sensitization (e.g., skin-prick testing [SPT] with common allergens).
2.3.1 Role of Commonly Used Objective Tests in Asthma Diagnosis in Children
2.3.1.1 Spirometry
The NAEPP guidelines
6
recommend conducting lung function testing to establish
reversible airflow obstruction. An FEV
1
of less than 80% predicted and/or FEV
1
/FVC
<65% or below the lower limit of normal are used to establish airflow obstruction.

8
Reversibility of airflow obstruction is documented with a ≥12% increase in FEV
1
after
using short-acting β2-agonist medication (e.g., albuterol, terbutaline).
2
However, the
Panel does not recommend conducting spirometry in children below 5 years of age,
and acknowledges that is often difficult to conduct testing in children below 7 years.
Furthermore, these tests can be abnormal in the presence of other respiratory
7, 8
and
even cardiovascular diseases
9
and as such are not specific for asthma. There can be
significant diurnal variation,
10
or the actual reduction in lung function may not be
detected in asthmatic children who are taking inhaled anti-inflammatory medications.
Use of standardized techniques and obtaining repeated lung function measures before
and after bronchodilator use can reduce measurement error, however, this would be
costly and may not be feasible in large, population-based epidemiologic studies.
11

Given these limitations of spirometry, diagnosis of asthma in early life still remains a
challenge and clinical diagnosis remains the mainstay of asthma diagnosis to date.
2.3.1.2 Testing for bronchial hyperresponsiveness (BHR)
Methacholine challenge test (MCT) is the most commonly used, well-established test
for determining bronchial hyperresponsiveness (BHR), an additional test
recommended to diagnose asthma if spirometry results are normal. Other tests of BHR
are available that uses different agents (e.g., histamine, adenosine, mannitol, exercise,
etc.). A 20% drop in FEV
1
between any two doubling concentrations of methacholine

9
(PC
20
) dose is used to determine BHR. Degree of BHR has been determined based on
dose of methacholine required to result in a 20% drop in FEV
1
(Table 2.1)

Table 2.1. Classification of bronchial hyperresponsiveness
PC
20
(mg/ml) Interpretation
>16 Normal
4.0–16 Borderline BHR
1.0–4.0 Mild BHR
<1.0 Moderate to severe BHR

BHR testing requires that an individual can perform spirometry adequately, and this
precludes effective use of this method in children who cannot maneuver spirometry
properly (ie, those below 5-7 years). In addition, BHR is not an exclusive feature of
asthma, as it can be positive in children without any asthma symptoms. Moreover,
children with wheezing episodes may not have BHR, and there can be significant
intra-individual variability or different responses to different agents used for BHR
testing.
12, 13
BHR varies with time, with increases observed during asthma
exacerbations and reductions during remission achieved with asthma medications.

Jenkins et al.

studied 164 children and compared the ISAAC questionnaire with the
BHR testing. The observed sensitivity and specificity for the ISAAC questionnaire
were 0.85 and 0.81 respectively.
14
Although the specificity with BHR testing was
above 0.90, the sensitivity was much lower (i.e., 0.54) and the positive predictive
value was 0.64. Even after combining BHR and questionnaire together, the sensitivity

10
was even lower (0.47). In Italy, using the ECRHS data, questionnaire data on ‘ever
asthma’ had high specificity (i.e., 0.975) and moderate sensitivity (i.e., 0.676).
15
The
achieved sensitivity and specificity observed by combining questionnaire information
and BHR were 0.486 and 0.986, respectively. The American Thoracic Society finds
that methacholine challenge testing is more useful in excluding a diagnosis of asthma
than in establishing one because its negative predictive power is greater than its
positive predictive power.
16

Therefore, testing BHR in children is not proven to be better in defining asthma in
epidemiologic studies than validated questionnaires.
17
Moreover, children may refuse
to participate if such an invasive procedure is performed resulting in smaller sample
sizes with concern for study validity and introduction of selection bias.
18

2.4 Classification of Childhood Asthma
There are different classification systems based on atopic status, disease severity and
natural history of disease. In this section, we will describe the classification based on
atopy status that describes asthma into two broad types: atopic and non-atopic asthma.
Classification according to disease severity categorizes asthma into mild intermittent,
mild persistent, moderate persistent and severe persistent based on asthma symptoms,
medication use and lung function evaluation.
1
This classification system is important
for initial patient evaluation and clinical management. However, it is not ideal for
epidemiologic studies, as it does not provide any information about the etiology of

11
asthma. Childhood asthma classification according to the natural history of the disease
defines asthma into early transient, early persistent and late onset asthma based on the
age at onset and persistence of wheezing.
19
We will discuss details of this
classification in the next chapter along with the natural history of asthma and briefly
describe the classification based on atopy status.

2.4.1 Atopic and Non-atopic asthma
Atopy is a hereditary predisposition to produce IgE antibodies against environmental
allergens. Atopy status is determined based on increased levels of total and specific
IgE in subject’s serum or from skin prick testing (SPT) in response to a battery of
different allergens (e.g., house dust mite, timothy grass, cockroach, etc.). Although
epidemiologic studies showed significant associations between atopy and asthma,
20-22

not all who are atopic have or develop asthma.
23

Peat et al.
24
examined the children of seven different areas in New South Wales,
Australia and observed that although about 35%-40% of children tested positive in
skin-prick testing, the prevalence of doctor-diagnosed asthma was lower. In Leipzig,
Germany, although the prevalence of atopy increased 9% over 4 years after
reunification of Germany, the prevalence of asthma in children remain unaffected
25, 26

(Table 2.2). Recently, pooling the data from 21 studies, Douwes et al.
27
showed that
eosinophil-mediated allergic airway inflammation is present in approximately 50% of

12
asthma cases and the rest of the cases have predominantly neutrophilic inflammation
with less than 4% eosinophils in sputum.

Table 2.2. Prevalences of skin-prick test (SPT) positivity and doctor-diagnosed asthma in selected
populations.
Country, year, age group
Ref.
Area N Skin-prick test
positive
(%)
Doctor-diagnosed
asthma
(%)
Australia, 1991-93, 8-11 years
24

Belmont
Broken Hill
Lismore
Moree / Narabi
Sydney
Wagga Wagga
West Sydney
926
794
805
770
1,339
850
904
39
37
35
40
42
40
42
38
30
31
31
24
29
28
Germany, 1991-92, 9-11 years
25
Leipzig / Halle
Munich
1,492
4,451
18
37
7
9
Germany, 1995-96, 9-11 years
26
Leipzig / Halle 2,331 27 7

Atopic and non-atopic asthma appears to have different risk factor profiles and
difference in phenotypic expression in terms of age of asthma onset. Atopic diseases
(such as eczema) and serum IgE at 9 months were more strongly associated with
early-persistent asthma phenotype than late onset asthma,
19
whereas obesity
28
and
personal smoking
29
have been associated with increased risk of non-atopic asthma in
adolescents. Taken together, these data suggest that classifying asthma on the basis of
atopy could provide important clues about the risk factors associated with these two
asthma subtypes and also may show differential risk factor profiles.

13
2.5. Environmental Influences on Pulmonary and Immune Developments
Because asthma is a chronic inflammatory disease that affects the airways, the
respiratory and immune systems are the two most important physiological systems that
are involved in asthma etiology. Before discussing the pathophysiological pulmonary
events in asthma, it is important to understand the growth and development of these
systems and to determine the effects of in utero and early life environmental exposures
on these systems that could underlie asthma etiology.

2.5.1 Environmental Influences on Lung Growth and Development
Lung development starts from the third week of intrauterine life and growth and
development of the lungs continues until the 2
nd
and 3
rd
decades of life.
30
The different
stages of lung development are shown in Table 2.3.
31, 32
In the embryonic stage, right
and left lung buds originate as outpouchings from the ventral wall of the foregut
leading to the development of trachea, principal bronchi, 5 lobes and 18 major lobules
by the end of this stage. Conducting airways are formed by successive branching of

Table 2.3. Different stages of lung growth and development in pre- and postnatal life.
Developmental stages Timeline Developmental features
Embryonic 3-7 weeks Lung buds

Pseudoglandular 5-17 weeks Formation of bronchi to terminal
bronchioles.

Canalicular 16-26 weeks Formation of respiratory bronchioles,
alveolar ducts, and capillary bed.

Saccular 26-36 weeks Primitive alveoli formation.

Alveolar 36 weeks- 2
nd
decade of life Alveolar maturation, dimensional
growth and microvascularization.

14
the lung buds at the pseudoglandular stage. Lining epithelium changes from pseudo-
stratified columnar to columnar in proximal airways and cuboidal in primitive acini.
This is followed by the canalicular stage when multiple generations of terminal and
respiratory bronchioles develop, with capillaries around them. Type II alveolar
epithelium begins to synthesize surfactant at this stage. The distal ends of respiratory
bronchioles enlarge during the saccular stage to form alveolar ducts and sacs. The
alveolar stage, which begins around 36th week of gestation and continues into young
adults, is marked by two key processes: (a) alveolarization and (b)
bronchovasculoalveolar interaction. During alveolarization there is thinning of the
alveolar walls and alveolar septation, which leads to an increase in the number of
alveoli. Vascular development occurs by development of new blood vessels from
mesodermal angioblasts (vasculogenesis) and by branching of existing blood vessels
(angiogenesis).
33

A complex series of tightly controlled systems that involve genetic (different growth
factors such as FGF, KGF, IGF, VEGF, PDGF, TTF1, TGF β1, etc), mechanical (fetal
breathing, amniotic fluid clearance), environmental (tobacco components, endotoxin,
ambient ozone), nutritional and endocrine (e.g., retinoic acid, corticosteroid)
influences and cross-talk between cells and mesenchyme are involved in lung
development and growth.
33-35
Most of the information about the role of these factors
on lung development and growth is obtained from animal studies, and is beyond the

15
scope of this literature review. However, effects of some of the exposures (implicated
in asthma etiology) on lung morphogenesis will be briefly addressed here.

Environmental exposures during both prenatal and postnatal periods may adversely
affect lung development. Studies have consistently observed that in utero exposure to
maternal smoking diminished childhood lung function.
36-42
In experimental models,
the effects of prenatal exposures to nicotine (a major compound in tobacco smoke) on
lung development has been examined. In animal models and cell cultures, nicotine
increased the expression α7 nicotinic acetylcholine receptors in lungs, affected lung
branching morphogenesis,
43
and induced lung fibroblasts to increase collagen
deposition leading to airway remodeling.
44, 45

Ambient air pollutants such as ozone and nitrogen dioxide (NO
2
)
46-50
or traffic related-
exposures
51
also adversely affect childhood lung function growth. Infant rhesus
monkeys (primates have similar distal airways as humans), cyclically exposed to
0.5ppm ozone had loss of three generations of conducting airways, 38% narrower and
45% shorter terminal bronchioles, and 41% narrower respiratory bronchioles
compared to those exposed to filtered air.
52
This study also found that the smooth
muscle bundle orientation around the last terminal bronchioles and the first respiratory
bronchioles was different between these exposure groups of infant monkeys.
Compared to animals exposed to filtered air, in those exposed to ozone, the percentage
of smooth muscle bundles oriented >30º from the perpendicular drawn along the long

16
axis of the airway increased whereas those oriented <15º decreased. In contrast,
opposite effects were found in first respiratory bronchioles where bundles oriented
>30º decreased and bundles oriented <15º increased. These changes in airway
development due to ozone exposure could explain the higher airway resistance
observed with ozone exposure in these animals
53
and in humans.
54
Given the
similarities between primates and humans in distal airway structure and lung function
responses from ozone exposure, it is possible that ozone exposure in early life may
impart similar morphological alterations in human airways.

In addition to ambient air pollutants, low dose endotoxin exposure could affect lung
morphogenesis in fetal lung in rats. Such exposure was associated with increasing
airway branching with an increased epithelial component, and increased expression
of surfactant protein C (SP-C), whereas high endotoxin dose prevented airway
branching and increased mesenchyme proliferation and apoptosis.
55
These effects
were mediated by immediate inducible nitric oxide (iNOS) dependent nitric oxide
(NO) production that was antagonized later by transforming growth factor β1
(TGF β1).

2.5.2 Environmental Influences on Immune Development
Immune development is a complex process and environmental exposures could
modulate immune functions in many ways, which is beyond the scope of this

17
review.
56-71
In the following sections, the major distinct cellular mechanisms that
different immunocompetent cells modulate in immune functions are described. The
“Hygiene Hypothesis”, which proposed that early life infections reduce asthma risk by
promoting T-helper cell type 1 (T
H
1) mediated immunity, has been briefly discussed
in this context of immune development. This is then followed by a summary of the
effects of environmental exposures on immune development. Similar to the earlier
discussion, effects of in utero exposure to maternal smoking, air pollution and
endotoxin exposures on immune functions are discussed.
2.5.2.1 Overview of the immune system
Conventionally, the human immune system is divided into two interlinked systems: (a)
the innate and (b) the adaptive immune system. The innate immune system involves
non-specific physical (e.g., cough reflex, mucociliary clearance, etc), cellular
(neutrophil, eosinophil, basophil, macrophage), and the chemical (i.e., histamine,
prostaglandins, leukotrienes, cytokines, reactive oxygen species, growth factors and
complements) and antimicrobial (defensins, cathepsin) products from such cells that
impart defense mechanisms which not only react immediately against offending
infectious agents but also modulate the development of the adaptive immune
system.
72, 73
The adaptive immune system has been classically divided into antibody
mediated (or humoral immunity) and cell mediated immunity. Different subtypes of
lymphocytes mediate these two principal arms of acquired host defense mechanisms.
The B lymphocytes, upon appropriate antigenic stimulus, transform into plasma cells

18
and secrete antigen-specific immunoglobulins (Igs) into the bloodstream and thereby
provide antibody-mediated immunity. The T lymphocytes, in contrast, do not produce
antibodies. Through their T-cell receptors (TCRs), they recognize processed antigens
presented by the macrophages and dendritic cells in the presence of major
histocompatibility complex (i.e., T-cells are MHC restricted), and provide host
defense either through direct contact with and eventual destruction of the pathogen or
by influencing the function of other immune cells. The T cells have surface proteins
called cluster of differentiation (CD) proteins, and based on these proteins T cells are
divided into cytotoxic T-cells (CTLs that carry CD8
+
) and helper T-cells (T
H
that carry
CD4). The CD4
+
T
H
cells are further categorized into T
H
1 and T
H
2 types based on the
cytokines they produce. Beside the T
H
1 and T
H
2 cells, regulatory T cells (Tregs) and
T
H
17 cells have been identified which play important role in immune modulations.
2.5.2.2 Innate Immune System
Recent advances in immunology have expanded our understanding of the innate
immunity to such an extent that a comprehensive summary of the effects of
environmental factors on different innate immune mechanisms in prenatal and early
childhood is beyond the scope of this review.
56-71
Among the innate immune
mechanisms, the toll-like receptor signaling pathway has received the greatest
attention in trying to understand the role of innate immune mechanisms in asthma
etiology.

19
In response to pathogenic microorganisms, dendritic cells (DCs), macrophages and
polymorphonuclear granulocytes (PMGs) recognize the pathogen-associated
molecular pattern (PAMPs) through the toll-like receptors (TLRs). Toll-like receptors
are a family of pattern recognition receptors (PRRs) that are highly conserved in
nature and provide defense against bacteria, viruses and fungi.
74
The TLRs are
transmembrane proteins and there are at least 10 different types present in mammals.
Their extracellular domain has leucine-rich repeats (LRRs) and the intracellular
domain is highly homologous to the intracellular signaling domain of the interleukin-1
receptor (IL1R).
75
Recent evidence suggests that TLR4 is mainly involved in
transmembrane signaling for the Gram-negative bacterial lipopolysaccharide (LPS)
and fusion protein for respiratory syncytial virus (RSV-F), whereas TLR2 acts as a
signal transducer for Gram-positive cell wall components such as peptidoglycan and
lipoprotein and lipoarabinomannan of mycobacteria and mannans of yeast.
76-79

In the presence of microorganisms, LPS binding protein (LBP) delivers LPS to CD14,
which is expressed either on the membrane of macrophages or granulocytes (mCD14)
or present in soluble form (sCD14).
80, 81
The signal is transduced sequentially via
myeloid differentiation (MyD) adapter protein MyD88, the interleukin-1 receptor-
associated kinase (IRAK-1, IRAK-2) and tumor necrosis factor receptor-associated
factor 6 (TRAF6) and I-kappa-B kinase (IKK) to activate nuclear factor kappa B (NF-
κB). Other components involved in this signaling cascade include mitogen-activated
protein kinases (MAPKs) such as extracellular signal-regulated kinase 1/2 (ERK1/2),
c-Jun N-terminal kinase (JNK), and p38 kinase. This signal transduction pathway

20
further coordinates the induction of multiple genes encoding inflammatory mediators
and co-stimulatory molecules.

Recent research indicates that innate immune mediators are involved in asthma
etiology. Mutation in the TLR-4 gene (i.e., Asp299Gly and Thr399Ile) blunted the
immune response in response to inhaled LPS.
82
In another study, adults with the wild-
type genotypes for these two co-segregating polymorphisms that code for the
extracellular domain of the TLR-4 protein had increased asthma prevalence, wheeze,
and BHR with increasing endotoxin exposure; whereas those with the variant
genotypes appeared to have reduced risk of asthma and BHR with increasing
endotoxin levels.
83
Polymorphisms in the CD14 gene have been associated with
reduced IgE levels,
84
and some studies observed significant positive associations
between the -159C>T polymorphism and asthma in children,
85, 86
while others did
not.
87, 88
Emerging data from epidemiologic studies have provided strong evidence that
the effects of CD14 functional variant on asthma and atopy (serum IgE, allergic
sensitization) vary significantly by endotoxin exposures
89-93
or surrogates of such
exposures (e.g., country living, farm milk consumption).
94, 95
Therefore, the null
findings between CD14 variant and asthma in some studies could have resulted from
not accounting for endotoxin exposures in the analyses.

21
2.5.2.3 Adaptive Immune System: T
H
1 vs. T
H
2 Polarization
When antigens are presented to the DCs and NKT cells, they secrete IFN- γ and IL-12
that via the transcription factors STAT4 (Signal Transducer and Activator of
Transcription 4) and T-bet (T-box expressed in T cells) polarize Naïve TH cells (T
H
0)
to T
H
1, and at the same time inhibit the conversion of T
H
0 to T
H
2 cells. However,
antigenic stimulation in the presence of IL-4 from mast cells, eosinophils and
basophils, promotes the development of T
H
2 cells. The key genes in this pathway
involve IL-4, STAT6, and GATA-3. The T
H
1 cells produce IL-2 and IFN- γ but T
H
2
cells preferentially produce IL-4, IL-5, IL-13 and other cytokines that promote mast
cell- and eosinophil-mediated responses, and therefore T
H
2 cells have been implicated
in asthma pathogenesis. T
H
1 and T
H
2 cells mutually down-regulate the development of
each other. The T
H
1 product IFN- γ impairs the generation of T
H
2 cells, and the T
H
2
cytokine IL-4 inhibits the development of T
H
1 cells.

2.5.2.4 The “Hygiene Hypothesis”
An increase in the prevalence of asthma and atopic disorder in the past few decades,
paralleled with a reduction in infectious disease prevalence in developed countries, led
Strachan to hypothesize that early life infection might be protective for asthma and
other atopic disorders.
96
The ‘Hygiene Hypothesis’ proposed that early life infection
skews the developing immune system towards T
H
1 mediated immunity and therefore
protects children from developing asthma; the latter being a T
H
2 mediated disease.

22
Although results from epidemiologic studies are not in agreement for all
epidemiologic markers of infections (e.g., sibship size, family size, daycare
attendance, etc.), the majority of these studies observed a protective role of larger
sibship size but not of daycare attendance. This suggests that the etiology of asthma
may be more complex than postulated by the Hygiene Hypothesis and that genetic
background and in utero and early life modulating effects of environmental exposures
on immune development may also play important roles.

Although the Hygiene Hypothesis formed the framework for identifying the
immunological etiology of asthma and other atopic diseases, data from recent studies
suggest that this hypothesis is an oversimplified approach to a much more complex
biological pathway. The inverse association between birth order, sibship or family size
and asthma has lent some support to the hypothesis that early life infection (i.e. T
H
1
response) protects against asthma. However, viral infections from respiratory syncytial

virus, rhinovirus, influenza and parainfluenza are associated with wheezing and
airway obstruction. Studies have also shown that both T
H
1 and T
H
2 cytokines are pro-
inflammatory
97
and their concentrations are often higher in subject with asthma. In
addition, prevalences of both T
H
1 and T
H
2 driven diseases have increased in
developed countries.
98
These findings suggested that other immune regulating
mechanisms could be a possible candidate to explain asthma pathogenesis.

23
2.5.2.5 Adaptive Immune System: Regulatory T-cells and Immunotolerance
Emerging body of evidence indicates that beside the T
H
1 and T
H
2 cells, T-regulatory
cells have distinct immunological functions. To date, four major types of regulatory T
cells have been identified: natural killer T (NKT) cells, CD4
+
CD25
+
cells, T
R
1 cells,
and Th
3
cells.
99
Sakaguchi and colleagues
100
first demonstrated that about 10% of the
peripheral CD4
+
T cells are regulatory T-cells, and they carry CD25 (i.e., these cells
are CD4
+
CD25
+
). In a mouse model, they showed that athymic mice inoculated with
CD4+ cells lacking CD25 molecule developed multi-organ autoimmune diseases. The
NKT cells are either CD4
+
or CD4-CD8- double negatives, and are involved in
allergen induced AHR by producing IL-4 and IL-13.
101
The CD4
+
CD25
+
cells express
IL-2 receptor α chain and contain two other cell surface markers: transcription factor
Foxp3 (forkhead box p3) and GITR (glucocorticoid-induced TNF receptor).
102, 103
The
suppression of immune mechanisms by these cells is mediated by cytotoxic T
lymphocyte antigen 4 (CTLA-4) and possibly by TGF- β but not IL-10.
99
Foxp3 has
been shown to be the key regulator in converting the naïve CD4
+
T to CD4
+
CD25
+

cells.
104
In a murine model, the CD4
+
CD25
+
cells inhibited airway eosinophilia and
T
H
2 immune responses (IL-4 and IgE levels) without any effect on AHR.
105, 106
The
T
R
1 cells are a subset of CD4
+
cells that develop in mucosal tissues (e.g.,
gastrointestinal epithelium) in the presence of IL-10 and produce high levels of IL-10
and low levels of IL-2, but do not produce IL-4.
107
These T
R
1 cells can suppress the
proliferation of CD4
+
cells in the presence of antigens and have been shown to
regulate T
H
1 and T
H
2 cells in vivo.
108, 109
The T
H
3 cells are subtypes of CD4+ cells

24
that Weiner and colleagues
110
first detected in mesenteric lymph nodes in mice after
oral antigen challenge with myelin basic protein. These T
H
3 cells produced TGF- β,
IL-4 and IL-10. Akbari and coworkers
111
have shown that DCs from mice that were
isolated from respiratory exposure to antigen produced IL-10 and promoted the
development of T
R
1 cells, whereas DCs isolated from intestine produced TGF- β and
induced T
H
3 development. These observations suggest that there may be preferential
development of regulatory T-cells. Because IL-10 has been shown to induce CD4
+
T-
cell tolerance in allergic asthma,
112, 113
T
R
1 cells may be involved in asthma
pathogenesis.
2.5.2.6 Adaptive Immune System: T
H
17 cells
Besides T
H
1, T
H
2, and Tregs, another T cell lineage called T
H
17

cells have been
recently identified.
114, 115
T
H
17

cells, which produce IL-17, are pro-inflammatory as
they are involved in neutrophil recruitment.
116, 117
IL-23 induces T
H
0 to differentiate
into T
H
17

cells in the absence of T
H
1 and T
H
2 promoting cytokines (IFN- γ and IL-4,
respectively).
115
To date, there are six different IL-17s (IL-17 A through F) have been
identified. IL-17 increases IL-8 release from airway smooth muscle,
118
IL-17A and
IL-17F are involved in the recruitment of neutrophils, whereas IL-17E (also known as
IL-25) is involved in T
H
2 cytokine production and eosinophilia.
119
In murine models,
T
H
17

cells have been found to amplify T
H
2 mediated effects (increase IL-4, IL-5, and
IL-13 production.
120, 121
T-cells and eosinophils in bronchoalveolar lavage and sputum
produced higher levels of IL-17 in individuals with asthma.
122-124
IL-17 is associated

25
positively with BHR,
125, 126
and is involved in increased expression of mucin gene
MUC5B and MUC5AC
127
Among the members of the IL-17 family, polymorphisms
in IL-17F were not associated with adult asthma;
128
however, effect of genetic variants
in IL-17 family of genes on childhood asthma remains to be investigated.

2.6 Pathophysiology of Asthma
Although reversible airway obstruction was once considered to be the main underlying
patholophysiologic event in asthma, recent advances demonstrated that chronic airway
inflammation, airway remodeling, and bronchial hyperresponsiveness (BHR) are
major underlying mechanisms in asthma pathophysiology.
2.6.1 Airway Inflammation
Airway inflammation is a key component in asthma pathophysiology. Bronchial
epithelium, dendritic cells, macrophages, mast cells, T-cells, eosinophils, and
neutrophils play important roles in airway inflammation. While epithelial cells,
dendritic cells, mast cells and macrophages are resident cells in the bronchial tissues;
T-cells, eosinophils, and neutrophils are recruited into the airways during the process
of inflammation.

Environmental exposures leading to oxidant stress plays a major role in airway
inflammation. A large body of evidence shows that exposure to ambient air pollutants
(i.e., ozone, sulfur dioxide, particulate matters, and diesel exhaust particles),
129-131

26
tobacco smoke,
132, 133
or allergens
134
can induce oxidative stress in airways. The
bronchial epithelium participates actively in the inflammatory processes by
elaborating various epithelial inflammatory mediators (i.e., cytokines, chemokines,
nitric oxide, arachidonic acid metabolites, growth factors, adhesion molecules).
Epithelial cells up-regulate the expression of intracellular adhesion molecule-1
(ICAM-1), and increase the synthesis of RANTES (Regulated upon Activation,
Normally T-Expressed, and presumably Secreted), interleukin-8 (IL-8), 15-
hydroxyeicosatetraenoic acid (15-HETE) and many other chemoattractants that aid in
the transmigration of leukocytes into the inflamed airways.
135-137
Bronchial epithelium
has been shown to express thymus and activation-regulated chemokine (TARC) or

CCL17, which may promote accumulation of T
H
2 cells in the airways.
138
Epithelial
cells in asthmatic airways have IgE receptors that can be activated by allergens.
139

Bronchial epithelial cells also express major histocompatibility complex (MHC) class
I and class II antigens and in the presence of allergens they can function as antigen
presenting cells (APCs).
135

Although bronchial epithelium participates in airway inflammation, mast cells and
leukocytes are the key effector cells in asthma. There are two phases in cellular
responses: an early phase response mediated mainly by mast cells followed by a late
phase reinforced by recruited leukocytes from peripheral circulation. The early phase
is triggered when allergen binds to immunoglobulin E (IgE) on mast cells in the

27
airway causing degranulation of mast cells. Histamine from mast cell granules causes
bronchospasm and increase vascular permeability. Cyclooxygenase and lipoxygenase
pathways are activated that produces prostaglandins (PGs) and leukotrienes (LTs).
PGD
2
, PGE
2
, PGF
2 α
, LTC4, LTD
4
, and LTE
4
also cause bronchospasm and increase
vascular permeability. Mast cells also synthesize different cytokines (IL-3, IL-4, IL-5,
IL-6, IL-8, IL-13, GM-CSF, TNF α) that promote T
H
2 mediated immune responses
and IgE synthesis. Different chemotactic factors (e.g., platelet activating factor,
leukotriene B4) recruit more leukocytes and a vicious cycle of inflammatory responses
continues. As a consequence of inflammation there is epithelial damage, goblet cell
hyperplasia with mucus hypersecretion, and edema in the airways.

2.6.2 Airway Remodeling
As the inflammation progresses the airways attempt to repair the damage by
depositing collagen underneath the basement membrane. This ‘subepithelial fibrosis’
has been linked to BHR and asthma severity.
140
Transforming growth factor- β1
(TGF β1) plays an important role in transforming fibroblasts into myofibroblasts that
have higher collagen synthesis compared to fibroblasts
141
and promote fibrosis by
inhibiting synthesis of matrix metalloproteinases (MMPs) and increasing the synthesis
of tissue inhibitors of metalloproteinase-1 (TIMP-1).
142
Moreover, there is airway
smooth muscle (ASM) hyperplasia in large airways and prominent hypertrophy of

28
smooth muscles in smaller airways.
143
This changes is ASM is also linked to asthma
severity and persistence.
144

2.6.3 Bronchial Hyperresponsiveness
Bronchial hyperresponsiveness (BHR) is another key component of asthma
pathophysiology. Clinically, BHR is measured by a decline in lung function (i.e.,
FEV
1
) following an inhalation challenge with a bronchoconstrictor agent such as
methacholine (described above). Compared to non-asthmatic individuals, the airways
of asthmatic individuals respond at a much smaller dose of the bronchoconstrictor
agent shifting the dose-response curve leftwards (hypersensitivity) and making the
slope much steeper (hyperreactivity).
145, 146

Airway smooth muscle (ASM) contraction is the major cause of airway narrowing in
asthma.
147
Histamine, prostaglandins, and leukotrienes, released during the process of
airway inflammation, can cause ASM contraction and bronchoconstriction.
148, 149

However, airway inflammation often does not correlate well with BHR.
147
Studies
have suggested that ASM hyperplasia and hypertrophy during airway remodeling may
determine BHR by increasing airway smooth muscle mass.
150, 151
Besides ASM
hypertrophy and hyperplasia, other events of airway remodeling tha increase airway
thickness, such as mucus hypersecretion, subepithelial fibrosis, and extracellular
matrix deposition, have been implicated in the etiology of BHR.
152-154
In a recent

29
study, Ward et al.
152
observed that airway inflammation and remodeling could account
for 40% of the variability in BHR. Besides airway inflammation and remodeling,
genetic predisposition is also an important determinants of BHR.
155, 156
Studies have
observed linkage between BHR and genetic markers on chromosome 5q
157
and the
gene encoding the β subunit of the IgE receptor on chromosome 11q.
158
Although
BHR is a fundamental component in asthma, it may be found in other disease
conditions such as cystic fibrosis and chronic bronchitis and even in non-asthmatic
individuals. Therefore, BHR is not specific for asthma. The relationship between
BHR, airway inflammation and asthma is not completely understood and currently
being under active research.

30
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44
Chapter 3: Descriptive Epidemiology of Childhood Asthma

3.1 Natural History of Childhood Asthma
Asthma prevalence and incidence are increasing in developed countries over the last
several decades. Asthma often starts in early childhood. Knowledge of the natural
history of asthma not only helps to identify potential demographic and environmental
risk factors but also is important to assess the prognosis of the disease in terms of
asthma persistence, severity, remission and recurrence or relapse all of which affects
asthma prevalence. Moreover, the International Study of Asthma and Allergies in
Childhood (ISAAC)
1
and the European Community Respiratory Health Survey
(ECRHS)
2
provided national asthma prevalence data for many developed and
underdeveloped countries that provided important clues to the etiology of asthma.

Many prospective studies conducted in developed countries such as the US, the UK,
Australia, and New Zealand provided information on secular trends in asthma
incidence and prevalence. Moreover, these studies also provided descriptive data on
various determinants for new onset asthma, asthma prognosis and prevalence.

3.1.1 Secular Trend in Childhood Asthma Incidence and Prevalence
Asthma in childhood years was not recognized as a major public health problem 50
years ago. However, currently it is considered as the most common chronic childhood

45
disease. Among Norwegian children, the cumulative incidence of asthma was 5.1% in
1985 and 8.6% in 1995, a 70% increase over 10 years.
3
In the British 1958 birth
cohort, cumulative incidence of wheezing increased with age; 18%, 24% and 43% at
ages 7, 16 and 33 respectively.
4
A similar trend in asthma incidence has been observed
in other developed countries of North America and Europe (Table 3.1).

Since prevalence of a relapsing-remitting disease such as asthma depends on both the
incidence and on the prognosis, factors that result in asthma persistence or recurrence
contribute to the increase in asthma prevalence. In the US, the greatest increase in
asthma prevalence has been observed in children below 5 years of age and between 5
and 14 years of age.
5
For example, asthma prevalence in US children below 5 years of
age has increased almost two-fold (i.e., 23 to 42.1 per 1,000) between 1980 and 1999.
5

A similar increasing trend in asthma prevalence is also seen in other developed
countries such as the UK, New Zealand, Australia and Canada (Table 3.2).
6-11

3.1.2 Geographical Variation in Asthma Prevalence
Although national prevalence estimates of asthma for different countries provided
some clues about the geographical distribution of asthma prevalences, comparison of
such data is difficult because each survey used different survey methods, age groups
and disease outcome (Table 3.1). The International Study of Asthma and Allergies in

46
Table 3.1. Major findings of some selected studies that examined the natural history of childhood
asthma
Population, age
year
Reference

Follow-up Major observations
UK, 1958 birth cohort
(n=18,559)
4, 12

Age 7, 11, 16, 23, and
33 years
Incidence of wheezing was 18%, 24%, 43% by age 7, 17
and 33, respectively.
Atopy, smoking, and male sex were associated with
incidence.
Asthma persistence: 50% and 27% at ages 7 and 33.

Australia, 1964 cohort
of 7 year-old children
with wheezing
(n=484)
13-15

7-year interval from
1964-99
Persistent symptoms resulted in reduced lung function.
Atopy, smoking and childhood disease severity
predicted asthma persistence.

UK, 1970 birth cohort
(n=11.486)
16

Age 5 and 10 years 50% of children diagnosed at age 5 had persistence of
symptoms at age 10.
80% with wheezing before 5 were asymptomatic at age
10.

New Zealand, 1972-73
birth cohort
(n=1,037)
17

Age 3, 5, 7, 9, 11, 13,
15, 18, 21, and 26
years
At age 26, 14.5% had persistent wheeze and 12.4%
relapsed.
Smoking, female sex, and atopy predicted persistence.
Early age at onset, and atopy predicted relapse
Lung function declined more in persistent wheezers.

Netherlands, 1972-76,
8-12 year old asthmatic
children (n=406)
18, 19

11.7-17.9 years of
follow-up
Childhood disease severity predicted adult disease.
Female sex and childhood responsiveness predicted
airway hyperresponsiveness.
76% continued to have symptoms despite treatment.

Sweden, 1974-75 birth
cohort (n=1,701)
20

18 months, and 3, 6-7,
10-11, and 11.5-14.5
years
Cumulative incidence at age 11 was 5.3%
Asthma was more common in children born between
August and October

US, 1980 Tucson birth
cohort (n=1,246)
21-24

Age 1, 3, 6, 8, 11, and
13 years
20% early transient wheezers, 14% persistent wheezers
and 15% late onset wheezers.
Lung function declined over time in persistent wheezers.
Maternal smoking and asthma predicted persistence.
Daycare attendance and presence of sibs at birth
increased transient wheezing but reduced persistent
wheezing at age 13.

Germany, 1990 birth
cohort (n=1,314)
25, 26

1, 3, 6, 12 and 18
months and age 2, 3,
4, 5 and 6 years
Cumulative incidence of recurrent wheezing by age 2
was 16.1% and was associated with maternal asthma
and atopy.
At age 2, boys had higher wheezing prevalence than
girls.
At age 7, doctor-diagnosed asthma prevalence was 6.1%

US, randomized
clinical trial, mild-
moderate asthmatic
children aged 5-12
years, 1993-95
(n=1041)
27

First arm: 311 with
budesonide and 208
with placebo;
Second arm: 312 with
nedocromil sodium
and 210 with placebo
Budesonide was relatively safe, improved airway
hyperresponsiveness and was better than nedocromil and
placebo.
Neither drug had any significant impact on lung
function.

Italy, cross-sectional
study, population age
0-44 years, 1998-2000
(n=18,873)
28

Collected information
retrospectively
Compared to 1953-1958, the incidence rate of asthma
increased 2.6 times in 1974-79.
Childhood asthma affected boys more and adult asthma
was more common in women.
Asthma persisted in adult life in 35% children.

47
Table 3.2. Trend in asthma prevalence in some developed countries
Country
Reference
Age group
(years)
Time
period
Measured outcome Prevalences (%)
United States
29
0-15 1980-94 Asthma attack in previous year 0-4: 2.2 - 5.8
5-14: 4.3 - 7.4
Boys: 3.2 - 5.1
Girls: 2.9 - 5.6

United States
30
5-17 1987-94 Parental report of asthma 9.2 – 15.9

Canada
10
5-14 1983-88 Physician diagnosed asthma Boys: 2.5 - 3.3
Girls: 1.5 - 2 .1

England
31
7-8 1978-91 Wheeze in past 12 months 8.8 - 11.6

England
32
12 1973-86 Persistent wheeze ever Boys: 0.8 - 2.1
Girls: 0.9 - 1.9

England
6
5-11 1982-92 Asthma attacks Boys: 4.2 - 11.8
Girls: 2.7 - 7.0
Persistent wheeze Boys: 3.2 - 4.4
Girls: 2.6 - 3.6

Scotland
6
5-11 1982-92 Asthma attacks Boys: 3.9 - 10.3
Girls: 2.1 - 5.9
Persistent wheeze Boys: 4.7 - 4.9
Girls: 2.6 - 3.3

Australia
33
5-14 1983-89 Recent asthma 3.3 – 8.3
1977-89 Chronic asthma 4.5 – 15.2

Australia
34
5-18 1984-92 Wheezy breathing 2.4 - 3.6

Australia
9
8-10 1982-92 Wheeze in past 12 months Belmont: 10.4-27.6
Wagga Wagga: 15.5-23.1

New Zealand
7
12-18 1975-89 Asthma in past year 5.1 - 8.0

Childhood (ISAAC)
1
and the European Community Respiratory Health Survey
(ECRHS)
2
were crucial in this respect that made international comparisons of asthma
prevalence possible.

The geographical variation in asthma prevalence does not always coincide with the
level of industrialization. However, in general, the ISAAC and the ECRHS data

48
showed that children living in the developed industrialized countries have the highest
asthma prevalence rates.
1, 2
For example, the highest asthma prevalence rates were
observed in the UK, Australia, New Zealand, and the US and the lowest prevalences
were observed in the Eastern European countries (e.g., Russia, Romania, Poland,
Estonia, Latvia, and Uzbekistan), China, Taiwan, and India. Moreover, much
difference in asthma prevalence existed within any specific country or geographical
region. In India and Kenya, for instance, there was a 5-fold difference in the 12-month
prevalence of self-reported asthma between the regions with the lowest and the highest
prevalences.
1
In Africa, the rates were much lower in Ethiopia than in South Africa.
Interestingly, asthma prevalences in Brazil, Peru and Costa Rica rivaled the rates in
English-speaking North American and European countries and were much higher than
the prevalence rates in Mexico and Argentina. Overall, increased prevalence in
English-speaking, westernized countries may be due to changes in lifestyle, levels of
ambient air pollutants, and household environment that occurred in the last several
decades. Regional variations within any particular country or continent may be
urban/rural difference in environmental exposures or lifestyle.

3.1.3 Migration Studies
The effect of migration on asthma can provide important clues in identifying the risk
factors for asthma. Only a few studies, to date, have examined the effect of migration
on asthma.
35-39
Peat et al.
35
observed lower asthma prevalence rates in children born

49
outside Australia who immigrated to Australia with their parents. Moreover, the
prevalence rate in children from Southeast Asian countries who immigrated into
Australia increased with their duration of stay in Australia.
36
Another Australian study
showed that the asthma prevalence rate among migrant children increased 11% for
each year of residency.
37
In Sweden, compared to children born in Sweden, Australia
and the US, those born in Eastern or Southern Europe or those whose mothers
emigrated from Eastern or Southern European countries had 50% lower hospital
admission rates for asthma.
38
Among adolescent age group, asthma prevalence was
much lower among Swedish conscripts born in African, Asian or Latin American
countries compared to other conscripts.
39
In this study,
39
the prevalence of asthma in
the draftees born in African, Asian or Latin American countries increased with their
duration of residency in Sweden. These results show that while asthma prevalence
among children and adolescent who migrated from an undeveloped to a developed
country increased over time, the rates are comparatively lower than the rates for native
children. One explanation that has been put forth for these findings is that children
born in developing countries around the world had greater probability of prenatal and
early life exposures to microbial compounds (e.g., endotoxin, beta-glucans) than
children born in western nations. Such exposures could promote balanced immune
development in respect to T
H
1- and T
H
2-mediated immunity, and thereby reduce
asthma risk later in life. Results from these Swedish studies provide some evidence
that both prenatal and early life exposures could be crucial in subsequent asthma
development.

50
3.1.4 Twin and Family-Based Studies
Although population based surveys and migration studies suggest a significant role of
environmental factors in asthma etiology, twin and family based studies have shown
that genetic predisposition is a strong determinant of childhood asthma and that
asthma may follow a polygenic/multifactorial inheritance pattern.
40
Higher
concordance rates have been observed in monozygotic (MZ) than dizygotic (DZ)
twins.
41-44
For example, one study reported concordance rates of 58.97% and 23.64%
in MZ and DZ twins respectively.
45
Linkage and association studies and genome-wide
screening showed that multiple genomic regions (i.e., 5q31-33, 6p21.3, 7p14-p15,
11q13, and 12q14.3-24.1) are associated with asthma.
46-49
Twin studies have also
shown that genes may determine lung function,
50-52
serum IgE,
53, 54
BHR.
54

Results from recent studies also suggest that gene-environment and gene-gene
interaction may be involved in asthma etiology. In a segregation analysis conducted
involving the families of children in Tucson Children's Respiratory Study, maternal
influence on child’s FEV
1
was greater than paternal influence in families where at
least one member had physician-diagnosed asthma.
55
In another study where children
had at least one asthmatic parent, asthma by age 5 years was more common in children
whose mothers were asthmatic compared to children with an asthmatic father.
56

However, in children diagnosed after age 5, parental asthma in either parent was
associated with similar more than 4-fold increased risk. In this study, the risk of
asthma doubled when both parents were asthmatic. These results suggest that a child’s

51
in utero or early life exposures (e.g., breastfeeding) from the mother may interact with
the susceptibility genes causing the phenotypic expression of the disease at an earlier
age. In recent years, many association studies using a candidate-gene approach have
identified several genes associated with asthma and also shown significant gene-
environment and gene-gene interactions – a discussion of such genetic determinants of
asthma is beyond the scope of this review.
57-80

3.1.5 Socioeconomic Status (SES) and Race
Asthma has been long recognized as a disease of the affluent societies. Data from the
ISAAC study, in general, agrees with this statement. However, in the US, asthma is
more prevalent in African-American and Hispanic communities with low SES. The
US national survey data shows that annual asthma prevalence, emergency department
visit and hospitalization is higher in African-American and other ethnic groups
compared to white children.
5, 29

The term ‘inner-city asthma’ was introduced to describe the asthma in economically
disadvantageous US minorities. Poverty per se may not an explanation for this inverse
association between asthma and SES. In Eastern Europe, for example, poverty is more
prevalent in farming communities where people follow traditional lifestyle. Children
living in those rural areas have lower prevalence of asthma.
81-83

52
In contrast, poverty or low SES in metropolitan US cities is more prevalent in
minorities (e.g., African-American, Hispanic, and Asian). According to the US census
bureau, in 2002, the poverty rates in non-Hispanic white, Asian, Hispanic and African-
American families were 8.0, 10.1, 21.8, and 24.1%, respectively.
84
As the poor
minority communities are located near the freeways, they are more exposed to
environmental pollutants and its harmful health effect, a concept referred to as
‘environmental injustice’.
85
In California, the African-American children were at three
times more likely to be exposed to pollutants from vehicular emissions compared to
white children.
86
Moreover, a significant percentage of minorities do not have health
insurance and adequate access to primary and preventive health care.
87-90

Lifestyle is also different among racial groups. For example, 45% of African-
American mothers breastfeed their child compared to 68% white mothers and those
who breastfeed stop breastfeeding in early weeks after childbirth.
91
Obesity is much
more prevalent in Hispanic and Africa-American children and is increasing over
time.
92-94
Recently, Gilliland et al.
95
observed that overweight and obese children had
52%-60% higher risk of new-onset asthma.

Indoor environment may also be related to this disproportionate asthma prevalence.
For example, presence of cockroach allergen, a risk factor for allergic sensitization
96

and asthma,
97
was found to be higher in poor African-American and Hispanic
communities.
98-100
Although lifestyle and environmental epiphenomena linked to

53
urban living conditions influence the asthma occurrence in inner-city children, there
may be some genetic determinants that may be responsible for such a differential
prevalence by race and SES.

3.1.6 Age of Onset and Age-Related Asthma Phenotypes
Although wheezing can start in the first year of life, Martinez et al. observed that
children with wheezing diagnosed as having asthma before age 3 may not have asthma
symptoms in later childhood.
21
Based on their observations of age at onset and
persistence pattern of wheezing, they proposed three asthma phenotypes: transient
early, late onset and persistent wheezers. Children were transient early wheezers if
they wheezed anytime in the first 3 years of life but not between age 3 and 6 years. In
this group of children wheezing illness was possibly due to respiratory viral infections
and maternal smoking affecting the developing smaller airways. At age 6, those
children with wheezing that started after age 3 were labeled as late onset wheezers and
those with wheezing episodes both before age 3 and at age 6 were labeled as persistent
wheezers.

3.1.7 Gender
Epidemiologic studies have consistently reported almost two-fold higher prevalence of
asthma in boys compared to girls before puberty.
101-105
Asthma incidence rate in
females surpasses that in male during young adulthood
106-108
and the early childhood

54
gender difference in asthma prevalence equalizes.
109, 110
In a Swedish cohort of
children between 7 and 8 years, boys were 70% more likely to develop incident
asthma than girls.
103
Data from the British1958 birth cohort showed that the M: F ratio
in asthma incidence reduces over time.
106
In this cohort, the male: female (M:F) ratio
during 0-7 years and 12-16 years of age was 1.23 and 1.48. However, between 17-23
years the ratio was reversed to 0.59. In a large population based survey of seven cities
in France, similar variation in asthma incidence by gender was observed.
108

Higher incidence rates of asthma in boys and adult women have been attributed to the
differential pulmonary growth pattern or ‘dysanapsis’ in boys and girls. Boys have
smaller airway diameter relative to their lung size compared to girls
111
greater
respiratory resistance and airway tone compared to girls.
112, 113
However, in adult life,
men have 17% larger airway diameter than adult women.
114
Standardized expiratory
flow rate and the ratio of

forced expiratory volume in one second (FEV
1
) to forced
vital

capacity (FVC) (i.e., FEV
1
:FVC) are used to assess dysanapsis and the indices are
lower in boys and women and higher in girls and men.

Several other explanations are also put forth to explain such an intriguing difference in
asthma incidence by gender and age. For example, boys have higher rate of respiratory
infections,
115
have greater sensitivity to allergens than girls.
19, 116
Results from the US
Nurses’ Health Study observed higher asthma occurrence in postmenopausal women
receiving hormone replacement therapy and the risk increased with the duration of

55
conjugate estrogen use.
117
Since estrogen and progesterone have been shown to
influence type-2 helper T cell (i.e., TH2) mediated immunity,
118
it is plausible that
female sex hormones may be involved in causing an increase in asthma incidence in
postpubertal period.

3.2 Determinants of Natural History of Childhood Asthma
Although earlier studies between 1930 and 1960 followed children prospectively for
many years in order to determine the clinical course of asthma, these studies mainly
involved asthmatic children with moderate of to severe symptoms attending
physicians’ offices or clinics.
119-122
Although some children of these studies had better
prognosis than others, most children had not. Since these studies were not population-
based, the whole spectrum of the natural history largely remained unknown. During
the last few decades, a few prospective cohort studies started following large number
of children into their adulthood. These studies have provided important information
about the factors that determine disease course into adulthood.

Asthma symptom persistence has been observed to be more common in adolescent
and adult females than males.
17, 123-125
The reasons are unclear but hormonal factors
have been implicated.
125
Results from large cohort study reported an increase in
asthma risk in women with increase in body mass since menarche.
126
Asthma
symptoms often increase during the course of pregnancy.
127
Maternal smoking during
pregnancy or infancy,
128
and active smoking during adolescence
123
are associated with

56
asthma persistence. Atopy and family history of asthma may also increase the risk of
persistence into adolescence.
21
In the 1958 British birth cohort, those who had
wheezing in the previous 12 months were two times more likely to be atopic.
4

Repeated chest infections,
129
and poor lung function during childhood
21, 130
may
predict persistence of symptoms. In the Tucson Children’s Respiratory study,
Martinez et al.
21
observed asthma persistence to be three time more common in
Hispanic children. Although the authors did not speculate as to the reasons for such
high asthma persistence rates among Hispanics, it is possible that living in low SES
communities located near busy freeways expose them to ambient air pollutants from
vehicular emissions.

3.3 Consequences of Childhood Asthma
Information about the clinical course of childhood asthma largely came from the large
birth cohort studies conducted in developed countries where asthma prevalence is
increasing over the last five decades (Table 3.1). In terms of prognosis, early onset
transient wheezers who do not wheeze after age 3 may have a favorable outcome.
Following children from birth to age 6, Martinez et al.
21
observed that 40.9% (i.e.,
164/401) of asthmatic children with early transient wheezing had no wheezing by age
6. In a retrospective study that examined asthma remission rate in subjects by age 44,
37.2% of asthmatic children diagnosed before age 10 had asthma symptoms within the
previous 2 years.
28
Kelly and co-workers followed 323 asthmatic children from age 7
to 28 and in their sample 32% continued to have wheezing at age 28.
131
Over time, on

57
an average 50% (30%-70%) of asthmatic children continue to suffer in adulthood.
121,
132
Almost 50% of asthmatic children who have a remission by adolescence develop
asthma recurrence in adulthood.
17, 110

Such persistence of symptoms is due to airway remodeling and bronchial
hyperresponsiveness that results in further airflow obstruction from subepithelial
fibrosis and bronchial hyperresponsiveness that ultimately leads to deterioration of
lung function over time.
133, 134
In Tucson Children’s Respiratory Study, lung function
improved in early transient wheezers, remained same in late onset wheezers but
declined in early persistent wheezers from age 1 to 6.
135
Studies have shown that
forced expiratory volume in 1 second (FEV
1
) declined 35-50 ml/year in asthmatic
children and adult.
136-141
In these studies, the annual decline in FEV
1
was greater in
adult asthmatics who smoked.

Although anti-inflammatory medications (e.g., corticosteroid and leukotriene
antagonists) could reduce airway inflammation, they may not modify airway
remodeling to such an extent to slow if not halt the disease progression. The impact of
asthma medications on lung function among mild to moderate asthmatic children was
evaluated in the Childhood Asthma Management Program (CAMP).
27
Although
asthma medications improved BHR and resulted in a better asthma control, neither
budesonide (corticosteroid) nor nedocromil (mast cell membrane stabilizer preventing
release of inflammatory mediators) had any significant effect on the lung function.

58
Taken together, the current evidence suggests that irreversible changes could occur in
subjects with persistent symptoms that result in progressive decline in lung functions.

3.4 Life Course Approach for Childhood Asthma
In the prenatal and early postnatal period, the immune system is in the process of
maturation. In this critical window of immune development, environmental exposures
may play greater immunomodulating role in the development of T
H
1 or T
H
2 mediated
immunity or immunotolerance. Studies suggest that childhood asthma risk may vary
by age at environmental exposures. In utero exposure to maternal smoking is
associated with higher asthma risk in children compared to secondhand smoke
exposure in postnatal life.
142
This suggests that the insult to pulmonary and immune
systems is greater when exposure occurred during the earliest stages of development.
Maternal asthma seemed to impart greater risk of early onset asthma and asthma risk
has been shown to be inversely associated with parity suggesting an important role of
in utero environment in asthma development in childhood.

Time of environmental exposures in postnatal life has recently been the focus of
research as studies have observed early exposure to endotoxin protects children from
asthma but exposure in adult life increases the risk especially in agricultural
settings.
143-147
In the farm environment, although all children were at reduced risk of
asthma, those who were exposed to stables and drank farm milk in the first year of life
were more than six times less likely to have a asthma diagnosis compared to children

59
who had such exposure after age 1 (odds ratios 0.14 and 0.88, respectively).
148
This
also shows that diet in infancy may be important. A recent clinical trial observed that
omega-3 polyunsaturated fatty acid supplementation from birth significantly reduced
the prevalence of wheeze in the first 18 months of life in children who had a first-
degree relative with asthma.
149
Results from another randomized clinical trial has
shown that cord blood of neonates born to atopic mothers who had fish oil
supplementation during pregnancy (i.e., in utero intake for the fetus) had significantly
higher EPA and DHA concentrations in their red blood cells and significantly lower
IL-13 levels in plasma.
150

Based on these recent observations, we hypothesize that the effects of exposures in
relation to different early life periods (i.e., in utero, infancy and childhood) may have
different impact on the developing pulmonary and immune systems. Therefore, a life-
course approach would be appropriate in epidemiologic studies and age at exposures
should be taken into consideration while assessing asthma risk.

60
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Chapter 4: Exposures and Events during Pregnancy and Childbirth and
Childhood Asthma

4.1 Introduction
Asthma is the most common chronic disease in childhood. The disease
disproportionately affects children. Prevalence in the United States is the highest
among children of 0-4 and 5-14 year age groups.
1, 2
Although asthma prevalence has
increased over several decades in developed countries, recent data suggest that the
increase in prevalence may have reached a plateau in some countries where high
asthma prevalences were documented in earlier time periods.
3-5
Nevertheless, it still
remains a significant clinical and public health problem that affects the lives of
children with asthma and impacts their family adversely. Despite considerable
research in this field, the etiology of asthma during early childhood remains to be
firmly established.

One of the difficulties in establishing asthma risk factors in children is the fact that it
is a heterogeneous disease that is diagnosed based on symptoms of wheeze, shortness
of breath, chest tightness and cough. However, for early childhood onset asthma, both
in utero and early postnatal exposures and experiences are likely to be important
factors in asthma pathogenesis. To better facilitate our understanding the
pathobiologies of asthma, several distinct asthma phenotypes based on child’s atopy
status (atopic vs. non-atopic asthma) and on age at disease onset and persistent of

74
wheeze symptoms (i.e., early transient, early persistent and late onset asthma) have
been examined. Because these asthma phenotypes may have different etiologies,
understanding the role of exposures and early life events on these asthma phenotypes
can provide better understanding of the pathophysiologic mechanisms involved in
each phenotypic entity.

A growing body of evidence indicates that both fetal and maternal factors could affect
fetal growth, immune maturation and lung development may affect asthma risk in
children. Maternal smoking during pregnancy has been consistently associated with
increased risk of asthma occurrence in children. In recent years, maternal dietary
exposures (vitamin D and E, omega-3 fatty acids, zinc) during pregnancy have been
associated with reduced risk of wheeze/asthma in children. In addition, maternal and
fetal adverse health events during pregnancy and labor, such as premature birth,
intrauterine growth restriction, and birth by cesarean section have been associated with
increased asthma occurrence.

Based on the evidence that in utero and at-birth exposures and events are important in
asthma pathogenesis, and that such factors may have different impact on the asthma
phenotypes, we set out to examine the relationships of these exposures and events with
childhood asthma including age at onset and atopy based asthma phenotypes.
Furthermore, we discuss possible biological mechanisms through which these
exposures could affect asthma risk in children. We have summarized the findings into

75
three sections based on the timing of these exposures/events. First, we have described
the “preconception factors” (e.g., maternal age, parity, oral contraceptive use before
pregnancy) that are likely to signify the effects of dynamic maternal hormonal and
immune functions on asthma occurrence. We then described the effects of common in
utero exposures on asthma. Finally, we reviewed the relationship of birth outcomes
with asthma. We acknowledge here that exposures during early childhood are also
likely to affect asthma risk in children; however, for brevity we have not discussed
those factors in this review.

Using MEDLINE and PUBMED, we searched for articles in English that were
published during the last 30 years (January 1976 to December 2006). However, for
asthma risk factors, which have been extensively studied, such as maternal asthma and
maternal smoking during pregnancy literature review was limited to articles published
during the last 10 years (i.e., between January 1996 and October 2006). We have not
considered postnatal exposures that occurred beyond birth (e.g., exposures to
secondhand smoke, childhood infections, infant feeding practices, childhood diet,
daycare attendance, and pet exposures) for this review.

4.2 Preconception Factors
The in utero period is a critical window where exposures and maternal conditions
could affect fetal growth and immune development. Maternal sex hormonal milieu

76
changes with age and immune responses also change with successive pregnancies. In
addition to endogenous hormones, exogenous hormone use (e.g., hormonal
contraceptive use) before pregnancy may also affect hormonal milieu and immune
functions. Thus, maternal age, parity, and oral contraceptive use before pregnancy
have the potential to affect asthma risk in children by modulating maternal immune
functions and altering the intrauterine environment.

4.2.1 Maternal asthma
Among all factors that could influence asthma risk in early childhood, family history
of asthma has been consistently found to be the strongest determinant. Maternal
asthma as well as asthma in first-degree relatives (father, sibs) has been associated
with 2 to 4-fold increased asthma risk; however, existing data do not strongly support
that maternal asthma differentially impact children’s asthma risk than paternal asthma.
Therefore, maternal asthma is likely to affect risk by increasing a child’s genetic
susceptibility in developing asthma. It is also plausible that variants in maternal genes
could interact with exposures during pregnancy (e.g., smoking, diet) to modify asthma
risk in the offspring; however, no study to date reported such associations. Maternal
asthma also increases the risk of adverse pregnancy outcomes (preterm birth,
chorioamnionitis, cesarean section), which have been associated with increased
asthma risk.
6-8
Further research is warranted to examine whether adequate asthma
control during pregnancy could prevent these adverse outcomes and whether

77
significant heterogeneity in asthma risk exists between children born to mothers with
and without well-controlled asthma during pregnancy.

4.2.2 Maternal age
Epidemiologic studies have found inconsistent relationships between maternal age and
asthma in children. Some studies found reduced asthma risk in children,
9-14
few found
increased risk,
15, 16
whereas others did not find any associations.
17-19
One explanation
for these inconsistencies across studies could result from not considering age at onset
based asthma phenotypes. Two studies
20, 21
found that maternal age was negatively
associated with early transient wheezing but was not associated with early persistent
or late onset wheezing. As early transient wheezing is likely due to viral infections, the
inverse association between maternal age and asthma in children may results from
reduced risk of early life infection in children born to older mothers.

4.2.3 Maternal Endogenous Sex Steroid Hormones
The sex hormonal milieu changes with age; however, detailed analysis of the effects
of maternal hormone levels on immune responses and on asthma in children is limited.
In a nested case-control study, Xu et al.
22
did not find any associations between
maternal first trimester levels of estradiol or progesterone and asthma in 5-6 year old
children. However, the authors acknowledge that levels in late pregnancy may be
more important than early pregnancy levels. In a birth cohort study, Xu et al.
23
found
that early maternal age at menarche was associated with increased risk of asthma in

78
adults (by age 31 years). In contrast, Maitra et al.
24
did not find any consistent
association between maternal age at menarche and asthma in children (by age 7 years).
These findings suggest that there could be differential risk by age at disease onset, and
that adult onset asthma may have a stronger hormonal etiology.

4.2.4 Maternal Use of Exogenous Sex Steroid Hormones
Exogenous hormones in the form of oral contraceptives (OC) may change immune
response. It has been shown that maternal use of progesterone during pregnancy
increased total serum IgE in cord blood.
25
The epidemiologic evidence of an
association between maternal OC use before pregnancy and asthma is limited. Using
ecologic data on OC sales, Wjst et al.
26
suggested that maternal OC use could be
associated with asthma occurrence in children. Using data from a sample drawn from
a cohort study conducted in Jamaica, Brooks et al.
27
found that maternal use of OC
was associated with asthma or wheeze risk (odds ratio (OR) = 1.8) and night time or
morning cough (OR = 2.7) in children. Children who had asthma/wheeze and also had
cough were at higher risk if their mothers used OC. The major limitations of this study
were lack of data whether OC was the last method of contraception before the index
pregnancy and how long before pregnancy the mother stopped using OC before
conception. Additional limitations of this study include low participation rate (60%)
and lack of information on parental atopy. Sunyer et al.
28
showed that women with
atopy are more likely to use OC and they delay their first pregnancy. Therefore, not
adjusting for maternal atopy may have resulted in a positive bias away from the null.

79
Taken together, these results are suggestive of an influence of maternal sex steroid
hormone levels and asthma occurrence in children. Further research with prospective
measurement of maternal hormone levels before and during each trimester of
pregnancy supplemented with information of exogenous hormone use may provide
stronger support that maternal hormone levels could influence asthma risk in children.

4.2.5 Parity (Birth Order/Sibship Size)
Several investigators have observed a reduced risk of asthma in children who had
higher birth orders,
29-31
but not all studies observed such a protective role of higher
birth order.
32-35
The protective effect of sibship size has been more consistent for atopy
than for asthma in most studies.
13, 17, 36-41
Westergaard et al.
30
found that higher sibship
size was associated with reduced atopic asthma risk but was not associated with non-
atopic asthma. In one study,
13
McKeever et al. observed that presence of older siblings
increased asthma risk in children below age two years but reduced the risk in children
diagnosed after two years. The same research group, however, did not observe any
role of early life infection in older siblings in asthma development in their index
cases.
42
Diagnosis of asthma by age 2 in this study may represent early transient
wheezing from respiratory illnesses. These data suggest that early life infections from
older siblings increase early life wheezing but could reduce asthma risk by skewing
immune responses to a physiologically appropriate T
H
1 mediated immunity.

80
The protective effect of parity/birth order on asthma has been explained both by
prenatal and postnatal factors. Among the prenatal effects of parity on immune
responses, researchers have shown that cord blood IgE levels and mononuclear cell
proliferative responses are reduced with higher birth order,
43-45
and maternal atopy is
inversely associated with parity.
46, 47
Postnatal immune modulation in children with
older siblings (i.e., higher birth order) follows the tenet of the “Hygiene Hypothesis”,
which postulates that exposure to microorganisms from contact with older sibling
favor the immune response towards T
H
1 mediated immunity, and thereby reduces risk
of asthma, which is considered to be a T
H
2 mediated disease.

4.3 Exposures/Events In Utero
Among the exposures during pregnancy, the relationship of in utero exposure to
maternal smoking with asthma has been investigated in many studies. In recent years,
data from well-designed pregnancy cohorts have shown that maternal diet during
pregnancy affects asthma risk in children. The associations between maternal
infections, medication use (including antibiotics), alcohol consumption, and exposures
to pesticides, allergens, and endotoxin and asthma have been investigated in a limited
number of epidemiologic studies.

4.3.1 Maternal Smoking during Pregnancy
In utero exposure to maternal smoking affects the development and function of the
respiratory system as it increases airway wall thickness,
48
increases airway

81
hyperresponsiveness,
49, 50
disrupts pulmonary neuroendocrine cell function,
51
and
reduces lung function at birth.
52
It also suppresses TLR mediated innate immune
responses
53
and enhances Th2 type immunity.
54, 55
Based on this evidence, it appears
that that maternal smoking increases asthma risk in children by affecting lung growth
and development and by modulating the immune responses in fetal life.

Maternal smoking has been consistently associated with asthma and/or wheeze
occurrence in children (Table 4.1). In a meta-analysis of papers published until 1997
(not included for review here), Strachan and Cook
56
reported that maternal smoking
was associated with an 31% increased incidence of wheezing up to age 6 (pooled OR
= 1.31, 95% CI: 1.22-1.41), but the association was weaker in older children (pooled
OR = 1.13, 95% CI: 1.04-1.22). Some of the studies that Strachan and Cook included
in their analysis did not differentiate between in utero and postnatal exposures.
Although this meta-analysis failed to detect any differential effect of timing of
exposure on asthma and whether quitting smoking before pregnancy minimized
asthma risk, subsequent research addressed these issues. Studies have reported that
children are not at statistically significant increased risk of asthma if their mothers quit
smoking during pregnancy.
57, 58
In addition, maternal smoking during pregnancy has a
stronger association with asthma occurrence than early life exposure to smoking.
59, 60

In a nested case-control study, Li et al.
57
found that children whose mothers smoked
throughout the pregnancy were at the highest risk of developing asthma by age 5
years. Dose-response relationship of number of cigarette smoked during pregnancy

82
and nicotine content with asthma have been examined in a few epidemiologic
studies.
57, 61
In a prospective birth cohort study, Magnusson et al.
61
found significant
dose-response relationship with numbers of cigarettes that the mothers used during
late pregnancy and wheeze but did not find any dose-response relationship for asthma.
Li et al.
57
also did not find any significant dose-response relationship between number
of cigarettes and asthma. Interestingly, these authors also found that among children
with in utero exposure to maternal smoking, those whose maternal grandmothers
smoked were at higher risk than those whose grandmothers did not. The authors
suggest that this transgenerational effect of tobacco smoke could be mediated by
epigenetic mechanisms.

Because smoking induces oxidant stress, functional variants in genes in the oxidant
stress pathway could modify the association between maternal smoking and asthma
occurrence in genetically susceptible children. Gilliland et al.
62
found that in utero
exposure to maternal smoking was associated with increased risk of asthma in children
who carried glutathione S-transferase M1 (GSTM1) null genotype. Further studies are
warranted to identify genes that may interact with maternal smoking during pregnancy
and increase asthma risk in vulnerable populations.

83
Table 4.1. Maternal smoking during pregnancy and asthma in children: Findings published during 1996-2006. *
Author
ref
, country Study design Subjects Major findings
Raherison,
58
France Cross-sectional N = 7242
4
th
-5
th
graders
Asthma: OR=1.22 (1.04-1.66)
Wheezing: OR=1.24 (1.10-1.56)
Prevalence: 21.6% (average 2 cigarettes per day)
Quitting in pregnancy: No increased risk
No effect from paternal smoking in adjusted model
Lannero
60
, Sweden Birth cohort N = 4089
followed 2 years
Doctor diagnosed asthma: OR =2.1 (1.2-3.7), mostly 1
st
and 2
nd
trimester
effects
Recurrent wheezing: OR = 2.2 (1.3-3.6)
Any wheezing: OR = 1.7 (1.2-2.4)
Prevalence: 12% (12%,10%, and 9% in 1
st
, 2
nd
, and 3
rd
trimester)
Jaakkola,
59
, Russia Cross-sectional N = 5951
8-12 yrs
Ever asthma; OR= 2.46 (1.19-5.08)
Current asthma: OR=2.55 (1.13-5.78)
Current wheezing; OR= 1.30 (0.90-1.89)
Chronic bronchitis: OR= 1.45 (1.08-1.96)
Prevalence: 4.3% (high ETS ~47%)
Postnatal ETS: associated with symptoms (wheeze, cough, phlegm),
infections, and allergy but not with asthma
Zlotkowska
63
, Poland Cross-sectional
(CESAR)
N = 1561
9-11 yr old
Ever wheezing; OR= 1.4 (1.0-2.0)
Asthma: OR= 0.7 (0.3-1.9)
Wheeze: OR= 1.3 (0.9-1.2)
Dyspnea with wheeze: 1.6 (1.1-2.5)
Under diagnosis: 2% asthma but 20% wheeze prevalence
Prevalence: 24.9% (average 9 cigarettes/d)
Magnusson
61
, Denmark Pregnancy cohort N = 7844
14-18 yr old
Wheezing before age 3: OR=1.2 (1.1-1.5)
Significant dose-response with number of cigarette
Asthma: No association or dose response
Hay fever/eczema: Inverse association
Prevalence: 41.5% (87% of them smoked throughout pregnancy)
Li
57
, USA Nested case-
control
N = 691
Asthma by 5yrs

Asthma: OR=1.5 (1.0-2.3)
Smoking throughout pregnancy confers highest risk
Prevalence: (19%,13%, and 12% in 1
st
, 2
nd
, and 3
rd
trimester)
No dose-response with number of cigarette
Grandmaternal smoking further increased risk
Quitting in pregnancy (15%): No increased risk

84

Table 4.1, Continued

Author
ref
, country Study design Subjects Major findings
Kurukulaaratchy
64
,
Isle of Wight
Birth cohort N= 1034 Persistent wheeze (onset by 4 and present at 10):
OR=2.44 (1.37-4.34)
Early transient wheeze (onset by 4 and absent since 9) : OR=1.58 (1.02-
2.45)
Prevalence: 39.6%
Jaakkola,
65
Finland Birth registry n = 58841
followed 7yrs
<10 cigarettes/d: OR= 1.20 (1.04-1.38)
>10 cigarettes/d: OR= 1.31 (1.09-1.58)
Prevalence: 15.5% (65.2% of them used <10 cigarettes/d)
Yuan,
66
, Denmark Birth cohort N = 9705
1 yr follow-up
Prescription for asthma (steroid + β agonist)
Ever/never: OR = 1.68 (1.35-2.10)
1-7 cigarettes/d: 1.45 (1.02-2.06)
8-12 cigarettes/d: 1.54 (1.13-2.09)
≥13 cigarettes/d: 2.10 (1.51-2.91)
Prevalence of maternal smoking during pregnancy: 28.4%
Chatkin,
67
, Brazil Birth cohort N = 981 sub-
sample 4-5yrs
Current asthma: OR=1.23 (0.93-1.61)
Current wheeze: OR=1.30 (1.01-1.66)
Prevalence of maternal smoking during pregnancy: 33%
Braback,
68
, Sweden Birth registry N=214276
(ICD493)
Hospital admission due to asthma
Admission 2-3 yrs:
1-9 cigarettes/d: 1.3 (1.1-1.5)
>9 cigarettes/d: 1.5 (1.2-1.8)
Admission >3 yrs:
1-9 cigarettes/d: 1.2 (1.0-1.4)
>9 cigarettes/d: 1.2 (0.9-1.5)
Prevalence of maternal smoking during pregnancy: 27.5%
Shohat,
69
, Israel Cross-sectional N=10057 (7436
Jewish/2621
Arab) 13-14yrs
Asthma: OR=1.21 (0.95-1.55)
Current wheeze: 1.30 (1.13-1.53)
Prevalence of maternal smoking during pregnancy: 5.4% in Arabs and
25.3% in Jews

85
Table 4.1, Continued

Author
ref
, country Study design Subjects Major findings
Gilliland,
62
, USA Cross-sectional N=2950 In children with GSTM1 null:
Ever asthma: OR=1.4 (0.9-2.1)
Active asthma: OR=1.7 (1.1-2.8)
Medication for asthma: OR=1.8 (1.1-2.8)
Early onset asthma: OR=1.6 (1.0-2.5)
Persistent asthma: OR=1.6 (1.1-2.4)
Ever wheezing: OR=1.8 (1.3-2.5)
Persistent wheeze: OR=2.2 (1.3-4.0)
Wheeze with exercise: OR=2.1 (1.3-3.3)
Medication for wheeze: OR=2.2 (1.4-3.4)
Emergency room for wheeze: OR=3.7 (1.9-7.3)
In children with GSTM non-null:
Ever wheezing: OR=1.3 (1.0-1.8)
Prevalence of maternal smoking during pregnancy: 16.2%
Sheriff
21
, UK Pregnancy cohort
(ALSPAC)
N=8594

Early infant wheeze (by 6 month):
Prenatal only: 1.5 (1.2-2.0); Both pre and post natal: 1.4 (1.2-1.7)
Persistent wheeze (at 6 and 30-42 months):
Prenatal only: 1.1 (0.7-1.8); Both pre and post natal: 1.3 (0.9-1.9)
Late onset wheeze (only at 30-42 months):
Prenatal only: 1.3 (0.9-1.9); Both pre and post natal:1.1 (0.9-1.5)
Prevalence of maternal smoking during pregnancy: 16.3%
Henderson,
70
, UK and
Czech Republic
Pregnancy cohort
(ELSPAC)
N =10683 for UK
and 3586 for
Czech Republic
Early infant wheeze (by 6 month):
Avon, UK: 1.30 (1.09-1.56)
Brno and Znojmo, Czech Republic: 0.99 (0.64-1.55)
Prevalence of maternal smoking during pregnancy: 17.5% in Avon, 7.1%
in Brno and Znojmo

86
Table 4.1, Continued

Author
ref
, country Study design Subjects Major findings
Gilliland,
71
, USA Cross-sectional N=5762 Asthma: 1.8 (1.1-2.9)
Active asthma: 2.3 (1.3-4.0)
Medication for asthma: 2.1 (1.2-3.6)
Wheeze: 1.8 (1.2-2.6)
Wheeze with cold: 2.1 (1.3-3.4)
Wheeze without cold: 2.5 (1.4-4.4)
Persistent wheeze: 3.1 (1.6-6.1)
Shortness of breath: 2.4 (1.3-4.4)
Awakened at night: 3.2 (1.7-5.8)
Wheeze with exercise: 2.4 (1.3-4.3)
Medication for wheeze: 2.1 (1.2-3.7)
Emergency visit for wheeze: 3.4 (1.4-7.8)
Prevalence of maternal smoking during pregnancy: 18.8%
Tariq
72
, Isle of Wight Birth cohort N=1218 Asthma by 4yr: 1.59 (1.10-2.31) [computed crude OR]
Wheeze:
At 1yr: 2.5 (1.7-3.7)
At 2yr: 2.2 (1.5-3.4)
At 4yr: 1.2 (0.3-2.7)
Prevalence of maternal smoking during pregnancy: 20.5%
Lux,
73
, UK Pregnancy cohort
(ALSPAC)
N=8561 Wheeze between 18-30
th
months: 1.19 (1.02-1.39)
Attributable fraction: 2.4%
Prevalence of maternal smoking during pregnancy: 16.2%
Stein
74
, USA Birth cohort
(TCRS)
N =1051 Current wheeze: 2.3 (1.4-3.8)
No effect on wheeze after age 3 years
Prevalence of maternal smoking during pregnancy: 19.5%
Rusconi
20
, Italy Cross-sectional
(SIDRIA)
N=16333
6-7yr old
Wheeze
Transient early (by 2 but not last yr): 1.33 (1.13-1.57)
Persistent wheeze (by 2 and in last yr): 1.77 (1.43-2.19)
Late onset wheeze (not by 2 but in last yr): 1.22 (1.00-1.49)
Prevalence: 14.8%
Gold,
75
, USA Birth cohort N=499 ≥2 wheeze in 1
st
yr: 1.83 (1.12-3.00)
Prevalence of maternal smoking during pregnancy: 6.4%

87
Table 4.1, Continued

Author
ref
, country Study design Subjects Major findings
Agabiti
76
, Italy Cross-sectional
(SIDRIA)
N= 18,737 6-7yr
and 21,068 13-
14 yr old
Among 6-7 yr old:
Current asthma: 1.62 (1.34-1.96)
Current wheeze: 1.31 (1.06-1.62)
Hu,
77
, USA Cross-sectional N=705 5
th
graders
Asthma: 1.9 (1.1-3.5)
Prevalence of maternal smoking during pregnancy: 23.4%

*Studies with less than 250 subjects available for analysis
78-81
and those that did not provide specific information on maternal smoking during
pregnancy
13, 19, 82-85
were not considered for review. Most recent papers were included for studies which were conducted on ongoing cohort and had
published multiple papers.
86-88
For results published before 1996, readers may review the paper by Strachan and Cook.
56

Abbreviations:

CESAR, Central European Study on Air Pollution and Respiratory Health.
NMIHS, National Maternal and Infant Health Survey, 1988 and Longitudinal Follow-up, 1991
ELSPAC, European Longitudinal Study of Pregnancy and Childhood
TCRS, Tucson Children's Respiratory Study
SIDRIA (Italian Studies of Respiratory Disorders in Childhood and the Environment)

88
4.3.2 Maternal Diet
The rise in asthma prevalence in western nations that was paralleled by decreased
consumption of vegetables (sources of antioxidants) and fish (source of omega-3 fatty
acids) prompted investigation into the role of antioxidants and lipids in asthma
occurrence. Data from animal models provide evidence that vitamin E and zinc are
involved in lung growth in fetal life.
89, 90
Vitamin E and zinc also modulate immune
functions in early life. Maternal intake of vitamin E during pregnancy reduces allergen
induced cord blood mononuclear cell proliferative responses.
44
In peripheral T-helper
cell culture, vitamin E down-regulates IL-4 gene expression by preventing the binding
of transcription factors nuclear factor κB (NF- κB) and activator protein (AP)-1.
91

ADAM33 (a disintegrin and metalloproteinase 33), a zinc-dependent asthma
susceptibility, is expressed in fetal lungs and is involved in lung growth.
92
It is
plausible that effect zinc deficiency could be mediated by altered function of
ADAM33 or other zinc containing proteins in fetal lungs.

Maternal vitamin E and zinc intakes during pregnancy have been associated with
wheeze and asthma occurrence in two pregnancy cohort studies in the US and UK.
93-95

However, maternal intakes of vitamins A and C, copper, magnesium, selenium, and
manganese were not associated with asthma in these studies. In the ALSPAC study,
cord blood selenium and iron levels were associated with reduced risk of persistent
wheeze and late onset wheeze, respectively.
96
In a nested case-control study, maternal
oily-fish consumption during pregnancy reduced asthma risk in children born to

89
mothers with asthma,
97
but had no impact on asthma risk of children with mothers
with asthma. In the same study, fish-stick (a source of trans fat) consumption was
associated with increased risk of asthma in children irrespective of maternal asthma
status. In the ALSPAC study, linoleic acid: α-linolenic acid ratio was associated with
increased risk of late onset wheeze.
98
Randomized clinical trials that tested the effect
of dietary avoidance of egg, cow’s milk and peanut during pregnancy did not find any
associations with asthma in children
99, 100
and fish-oil supplementation or fish intake
(sources of omega-3 fats) in early childhood was not associated with asthma in
children.
101, 102
However, a growing body of evidence indicates that supplementation
of maternal diet with omega-3 PUFA
103
or maternal fish intake during pregnancy may
reduce the risk of early life asthma occurrence, especially in genetically susceptible
children.
104, 105

These data suggest that maternal intake of antioxidant vitamins and omega-3 fatty
acids could reduce asthma risk in children. The protective effect of omega-3 fatty
acids on asthma could be mediated by reducing allergic sensitization in children,
104

reducing oxidant stress,
106
and down-regulating T
H
2 mediated immunity.
104
Because
of these important anti-inflammatory properties of antioxidants and omega-3 fatty
acids have, diet rich in these nutrients may affect asthma risk. Few pregnancy cohorts
have examined the effects of maternal dietary intakes of fats (omega-3 and omega-6),
antioxidants vitamins (e.g., vitamins A, C, and E), and trace elements (zinc, copper,

90
magnesium, selenium, iron, and manganese) during pregnancy on early life wheeze
and asthma occurrence in children.

4.3.3 Maternal Alcohol Consumption
Alcohol consumption during pregnancy have been associated with increased cord
blood levels of IgE
107
and inflammatory cytokines IL-6, TNF-α, and IL-1 (both α and
β).
108
In addition, the in vitro component of the latter study showed that the
stimulatory effect of LPS on these cytokine productions from maternal and fetal cord
blood lymphocytes was blunted in a dose-response fashion by alcohol and this
blunting effect were pronounced in the fetus.
108
In animal models, chronic alcohol
exposure have been associated reduced glutathione levels and increases permeability
of the airway epithelium.
109, 110

Epidemiologic evidence for an association between maternal alcohol consumption and
asthma is limited. In a Danish study of over ten thousand children who were followed
from birth ( ≥36 weeks of gestation at birth) to 9-12 years, maternal alcohol
consumption was not associated with asthma hospitalization.
111
Retrospective recall of
alcohol consumption rather than collecting the data during pregnancy likely resulted in
exposure misclassification.
112
In addition, asthma hospitalization reflects a form of
severe asthma and may not be an appropriate endpoint to assess the effect of maternal
alcohol consumption on asthma. Further research is warranted to examine the impact
of maternal alcohol use on asthma in children.

91
4.3.4 Maternal Infections and Antibiotic Use
Maternal bacterial, viral, and fungal infections during pregnancy have been associated
with asthma occurrence in children.
113-115
Some of these studies explored the effect of
vaginal infections on childhood asthma.
113, 114
whereas other studied relationship of
maternal systemic infections. Based on hospital and prescription databases, Benn et
al.
113
observed that maternal vaginal colonization with Ureaplasma urealyticum
during 8-24 weeks of pregnancy was associated with 2-fold increased risk of asthma
hospitalization by age 3 years but was not associated with asthma medication use at 4-
5 years. For asthma hospitalization by age 3 years, children with maternal allergic
disease were at greater risk. Among 8,088 Finnish children born during 1985-1986,
Xu et al.
114
found vaginitis was associated with 41% increased risk of asthma by age 7
years. Vaginitis due to Candida (most common cause of vaginitis in this population;
~87%) and Chlamydia showed significant associations with asthma in offspring,
whereas vaginitis due to gonococcus was marginally significantly associated. Among
systemic infection, McKeever et al.
116
found that gastrointestinal and respiratory
infections were associated with 20% and 29% increased risk of asthma in children,
respectively. Although specific microorganisms were not tested, viral, bacterial and
candidal were associated with increased asthma risk in offspring.

Maternal antibiotic use during pregnancy was also associated with increased asthma
occurrence in children in some studies.
113, 116, 117
McKeever et al. found a statistically
significant dose-response relationship between number of prescribed antibiotics and

92
asthma and wheeze incidence.
116
Rusconi et al.
117
found that antibiotics for respiratory
tract infections was associated with increased risk of persistent (OR=2.91; CI:1.73-
4.86) and late onset wheezing (OR= 2.25; 95% CI: 1.32-3.83) but not associated with
early transient wheezing. However, antibiotics for urinary tract infection were
significantly associated with increased risk of early transient wheezing (OR = 1.57;
95% CI: 1.20-2.06). Maternal antibiotic use at birth was associated with early transient
and early persistent asthma but not with late onset asthma.

Data from these studies suggest that genitourinary tract infections are associated with
early transient asthma phenotype. It is possible that this effect is mediated by airway
inflammation resulting from colonization of microorganisms in respiratory tract in
utero or at birth. Because genitourinary tract infections could result in
chorioamnionitis and antibiotics can cross placental barrier
116
and affect maternal
microbial load,
117
the effects of genitourinary tract infections on asthma may vary by
antibiotic usage, which remains to be investigated. Further studies should examine the
effects of specific species of microorganisms and specific class of antibiotic on asthma
occurrence in children.

4.3.5 Other Maternal Medication Use
Among the other medications, associations between maternal use of acetaminophen
and corticosteroids on asthma occurrence have been examined in several studies.

93
Acetaminophen is prescribed to reduce pain during pregnancy. Steroids are given to
mothers who experiences pre-term labor for ensuring lung maturation in the fetus.

In two papers, using data from the Avon Longitudinal Study of Parents and Children
(ALSPAC) study, Shaheen et al. found that frequent acetaminophen use between 20-
32 weeks of pregnancy was associated with increased risk of wheeze by 30-42
months
118
and wheezing, asthma and elevated IgE by 7 years.
119
Acetaminophen use
between 18-20 weeks of pregnancy and aspirin use during pregnancy were not
associated with asthma or IgE levels.

Because the increase in asthma prevalence coincides with introduction of
corticosteroids in preterm birth to reduce neonatal respiratory morbidity and because
preterm birth has been found to be a risk factor for asthma occurrence in children,
several studies examined the role of antenatal corticosteroid therapy on respiratory
outcomes. These studies yielded mixed results. In a cohort study of 477 infants born
<33 weeks of gestation in Western Australia, French et al.
120
found repeated steroid
therapy during pregnancy was associated with reduced birth weight and children born
to these mothers were more likely to have chronic lung disease in neonatal period. In a
hospital based matched (on sex, gestational age, and year of birth) case-control study
involving 28 pairs, Hasbargen et al.
121
did not find any association between repeated
antenatal corticosteroid therapy (>5) and asthma, allergy, or upper respiratory tract
infections compared with children who received ≤1 antenatal corticosteroid therapy. In

94
another study of 384 children who had very low birth weight ( ≤1500g), antenatal
corticosteroid therapy was associated with a borderline protective effect on wheeze in
previous 12 months (OR=0.56; 95% CI: 0.29-1.1) but was not associated with asthma
among 8-year old children.
122
Most of these studies were based on small and/or
convenience samples and the investigators did not considered potential confounders.
Therefore, no firm conclusion can be reached at from these studies and further
research is warranted.

4.3.6 Maternal Psychological Stress
Parental or caregiver stress during early life (2-3 months of age) has been associated
with increased wheezing in infants;
123
however, prospective study on the effect of
maternal stress during pregnancy and asthma/wheeze outcomes in children have not
been reported to date. In a pregnancy cohort, Clougherty et al.
124
found that children
exposed to traffic related pollution between age 4 and 11 years were at high risk of
asthma only when they were exposed to violence. Lin et al. found that maternal stress
was associated with increase cord blood IgE.
125
In animal models, prenatal stress was
associated with increased airway inflammation
126
and BHR.
127
In adult asthmatics,
stress was associated with asthma exacerbation and increase in pro-inflammatory
cytokine (e.g., TNF).
128
Wright proposed that maternal stress during pregnancy could
affect both maternal and fetal immune and neuroendocrine systems (especially the
hypothalamic-pituitary-adrenal (HPA) axis)
129, 130
and may increase asthma risk.
131

Although it is plausible that caregiver stress in postnatal period could be highly

95
correlated with prenatal stress level and that the effect on immune and HPA axis may
be mediated in utero, prospective studies where maternal stress levels are measured
during pregnancy are need to examine the role of prenatal stress on asthma occurrence
in childhood.

4.3.7 Environmental Exposures
Environmental exposures that can induce oxidant stress and/or cross the placental
barrier could be associated with disturbances in immune and respiratory development
in fetus and lead to increase risk for asthma. Epidemiologic studies have examined the
effects of pesticide, allergens and endotoxin exposures during pregnancy and asthma
occurrence in the offspring.

4.3.7.1 Pesticide exposure
Dichlorodiphenyldichloroethylene (DDE) levels at birth but not at 4 years was
associated with increased wheeze and asthma at age 4 years
132, 133
In a study among
children participating in the ALSPAC study, Sherriff et al.
134
formulated a chemical
burden score (range: 0 to 55) based on maternal use of 11 different chemical products
during pregnancy and their frequency of use (scored 0 to 5: never use to everyday
use). The study found that children born to mothers who were exposed to the highest
decile of chemical household products during pregnancy were at 2.3-fold (95% CI:
1.20-4.39) increased risk of early persistent wheeze than those exposed to the lowest
decile in utero. No single chemical product was implicated and there was no

96
significant association with early transient and late-onset wheeze. Although 21.2%
children were exposed to pesticides or insect killers in utero, the authors did not
evaluate the association between chemical burden score and wheeze by
pesticide/insect killer exposure.

4.3.7.2 Allergen exposure
Allergic sensitization in fetal life resulting in higher IgE levels in cord blood (CB) has
been investigated as a predictor of asthma and other atopic diseases. However, cord
blood IgE levels had little predictive value on asthma. Results from observational
study used different cut-points to define high CB IgE and the results from these
studies are inconsistent (Table 4.2). A systematic review of clinical trials also did not
find any significant effect of maternal allergen avoidance during pregnancy and atopic
disease outcome in early childhood.
135
Studies have shown that chromosome 5q31.1
appear to regulate IgE production
136, 137
where some of the asthma susceptibility genes
(e.g., IL-4, IL-5, IL-9, CD14) are located. In addition, Arg130Gln polymorphism in
IL-13 gene was associated with increased CB IgE levels.
138
Therefore, further research
is warranted to determine whether functional variants in these genes could identify
susceptible children who could get benefit from such allergen avoidance strategies.

97
Table 4.2. Cord blood IgE and asthma or wheeze occurrence in children.
Author, ref Study design Subjects Findings
Goldstein,
139
Birth cohort N=321 mothers
and 291-137
children
Poor correlation between CB total IgE
and maternal and early childhood
levels 2- and 3-yr (r<0.2)
No association with asthma or wheeze
outcomes

Sadeghnejad
140
Isle of Wight birth
cohort
N=1358 CB IgE was not associated with
asthma by 4 yrs but was associated
with asthma at 10 years (OR 1.66,
95% CI 1.05 to 2.62)

Lopez,
141
Birth cohort followed
1 year
N=102; Total IgE and specific IgE to cow’s
milk, HDM, and egg white were
associated with recurrent wheeze in the
first year of life

Sunyer,
142
Birth cohort followed
for 4 years
N= 528, Nigerian,
RCT for
malaria/anemia
Used 1.9kU/L as cut off for high CB
IgE, which was inversely associated
with current but not with recurrent or
frequent wheeze.

Kaan,
143
Birth cohort (clinic
based), family history
of allergy
N = Followed for
12m
CB>0.5kU/L was associated with
urticaria due to food allergy but not
with asthma, rhinitis, atopic dermatitis,
or positive SPT.

Tariq,
144
Isle of Wight birth
cohort
N = 1218 CB IgE (using 0.5kU/L cut off) was
not associated with asthma by age 4
years

Lodrup Carlsen,
79
Nested case-control
study, from Oslo Birth
Cohort
N = 165 Children with recurrent/persistent
wheeze had higher CB IgE levels

Edenharter,
145
Birth cohort (MAS) N = 1314; 5yr
follow up
CB IgE was associated with allergic
sensitization by 12 months
No association with recurrent
wheezing

Croner
146
Birth cohort; N =1654 N = 59 CB IgE was not associated with
asthma by age 11 years

4.3.7.3 Endotoxin exposure
Studies have found that children who were raised in farms have lower risk of asthma.
While this has been explained more as a postnatal effect mediated by endotoxin
exposure from farm animals, it could be a prenatal effect, which is mediated by

98
maternal exposures to endotoxin in farm settings during pregnancy. Recently, Ege et
al.
147
have found a dose-response relationship between numbers of different species of
animals that the mothers had contact with during pregnancy and expression of innate
immunity genes (CD14 and toll-like receptor (TLR) 2 and TLR4) in their children
aged 5-13 years. These authors also reported that maternal exposure to farm-related
exposures (i.e., farm milk consumption, exposure to animals, work at stables, etc.)
were associated with reduced risk of atopic sensitization, wheeze and asthma.
Although this study provided evidence that exposure to microbial products during
pregnancy may modulate immune responses in fetal life and affect asthma risk in
children, it appears that gene expressions differed by specific exposures in farm
environment. The authors adjusted for number of older siblings in their analysis, but
did not evaluate whether the associations varied by sibship size, which could provide
some suggestions as to whether the effects of hormonal milieu modified the effect of
farm exposures on asthma. In addition, the role of allergen exposures, which is also
common in farms, was not examined in this study. More research is warranted to
examine the independent and possible synergistic effects of endotoxin and allergens
on asthma development in early childhood.

4.3.7.4 Exposures to Ambient Air Pollution and Traffic
Although early childhood exposure to air pollution has been associated with asthma
occurrence (especially traffic related pollutant) and exacerbations, the effect of
prenatal exposures to pollutants on childhood asthma has not been reported to date.

99
Hamada et al.
148
found that prenatal exposure to air pollution in pregnant BALB/c
mice resulted in increased BHR in the offspring when exposed to allergen after birth,
promoted T
H
2 skewed immunity and pathological changes in their lungs which are
characteristics of asthma (allergic airway inflammation with eosinophil and
macrophage infiltration and goblet cell hyperplasia in the airway) compared to mice
born to unexposed mothers. In another study, Fedulov et al.
149
found that exposure to
DEP or even inert carbon black or titanium oxide (TiO2) particles during pregnancy
led to differential gene expression compared to non-pregnant mice, and led to
increased allergic airway inflammation in the offspring. These animal studies provide
some insight into the pathophysiologic mechanisms by which in utero exposure to air
pollutants may affect asthma occurrence in children. Few epidemiologic studies also
showed the association between traffic related exposures and asthma was stronger in
children who did not move from their residence at birth (i.e., lifelong residents). This
finding may indicate that the effect of air pollution on asthma could be mediated in
utero. Further research is warranted to evaluate the associations between prenatal
exposures to ambient and traffic related pollutant and asthma occurrence in children.

4.3.8 Other Pregnancy Related Factors
In a case-control study, threatened abortion during the second trimester was associated
with increased asthma occurrence (OR 2.06; 95% CI 1.07-3.94) in children.
115
Women
with threatened abortion were more likely to be prescribed isoxspurine (a tocolytic

100
agent) and this drug use was also associated with increased asthma risk (OR 1.54; 95%
CI 1.08-2.19). In a British cohort of over 4000 children aged 18 years or younger,
Annesi-Maesano et al.
150
observed that threatened labor (prevalence 4.8%) and
malposition/malpresentation (prevalence 1.8%) of the fetus were significantly
associated with asthma.

Maternal hypertension/preeclampsia was associated with 5% increased risk of asthma
(95% CI: 1.00-1.10) by age 6 years in a large study in Manitoba, Canada where all
children had universal access to healthcare.
16
In another study, Rusconi et al.
117
found
that preeclampsia was associated with 40% to 59% increased risk for age at onset
based asthma phenotypes (i.e., early, persistent and late onset wheezing).

Few studies examined the role of amniocentesis or chorionic villus sampling and
previous abortion, miscarriage, and stillbirth on asthma.
116, 117
Although McKeever et
al. found previous miscarriage was significantly associated with increased risk of
asthma; the results were not statistically significant after adjusting for consulting
behavior of the child. Short inter-pregnancy interval ( ≤2 years) has been associated
with reduced risk of atopy
151
and hay fever,
14
but has not been significantly associated
with asthma.
14

Among few other maternal conditions, maternal weight gain during pregnancy was not
associated with wheeze;
117
however pre-pregnancy obesity was associated increased

101
asthma risk by age 3 years.
152
Maternal diabetes was associated with increased risk of
early persistent wheezing but was not associated with early transient or late onset
wheezing.
117
Maternal depression during pregnancy was associated with asthma, hay
fever and eczema. The effect of depression could be mediated by maternal stress
mediated increase in IgE and a establishing a predominantly Th2 mediated immune
response offspring.
125, 126

4.4 Birth Outcomes
Among the events during birth, effect of birth by cesarean section on asthma
occurrence in children has received the most attention in epidemiologic studies. A
parallel increase in asthma and cesarean section prevalences in developed countries
suggests a possible role of cesarean section in asthma etiology. Apart from this event,
few studies evaluated the role of labor induction, other assisted delivery methods, and
multiple pregnancy on asthma.

4.4.1 Birth by Cesarean Section
In prospective birth cohort studies involving children born before 1990,
17, 153-155
birth
by cesarean section was associated with increased asthma risk in offspring (Table
4.3). For example, Xu et al.
153
found that birth by cesarean section was associated with
a 3-fold increased asthma risk by age 31 in individuals born in 1966. However, birth
cohort studies conducted in children born after 1990 who were followed up to 5-7
years did not find any significant associations.
156, 157
Data from retrospective cohort

102
are inconsistent and cross-sectional studies did not find any associations. Earlier
studies that found significant associations did not differentiate between emergency and
elective cesarean sections. It is possible that a larger proportion of children were born
by emergency cesarean section during that period. The underlying fetal-maternal
complications that indicated an emergency cesarean section and/or ancillary obstetric
and anesthetic management could have resulted in an increased asthma risk as was
found in those earlier studies.

Although the mechanisms by which cesarean section may affect asthma occurrences is
not completely understood, there are several biologically plausible mechanisms by
which events related to cesarean section may affect asthma occurrences in children.
Cesarean section has been shown to delay and alter the development of intestinal
bacterial flora in infants.
158
This may, in turn, alter immune development and
subsequently increase the risk of atopic disease in children. In addition, women and
unborn children requiring C-section are more likely to have deliveries complicated by
intrauterine infection or chorioamnionitis. Such intrauterine exposure to microbial
antigens and the associated immunologic stimulation has been suggested to increase
risk of asthma.
116
Finally, children born by cesarean section are at increased risk of
respiratory distress syndrome (RDS), transient tachypnea of newborn (TTN),
159
and
food allergy,
160
and have increased IL-13 levels compared to children born
vaginally.
161
All these factors could also increase asthma risk in children born by
cesarean section.

103
Table 4.3. Review of papers that examined the association between Caesarean section delivery and asthma
Author Study design Birth
year
Subjects Findings Comments
Xu
153
Birth Cohort,
Northern Finland
1966 1,953 of the 12,058 births
with complete atopic and
obstetric histories.
OR
by age 31
= 3.23 (1.53-6.80) No association with atopy, hay
fever and atopic eczema. CS
prevalence was 5%
Bager
17
Danish national Birth
Cohort
1973-77 9,722 women between 20-
28 yrs of age
OR
ever
= 1.33 (1.02-1.74)
OR
current
= 1.22 (0.87-1.73)
CS prevalence was 5.1%,
Not adjusted for maternal asthma
Xu
154
Birth
Cohort, Finland
1985 8,088 children OR
by age 7
= 1.38 (1.00-1.92)
Kero
155
Finnish Birth Cohort 1987 99.9% of All live births in
Finland in 1987 (n =
59,865)
OR
by age 7
= 1.21 (1.08-1.36) Birth weight explained 22% higher
prevalence in CS group, CS
prevalence was 14.7%
Kero
155
Turku Birth Cohort 1990 Random sample of 113
children born by CS and
106 born vaginally; all
term-births
OR = 1.5 (NS)
OR
SPT+
= 1.3 (NS)
No difference in IgE
Low participation rate (around
70% for asthma and 60% for SPT
& IgE), EBF more in VD group
Maitra
156
Birth cohort
ALSPAC
1991-92 12367; 7-yr follow up OR asthma by 91 months
1.14 (0.9-1.4)
Prevalence: 11.2%
Included preterm and LBW babies
Nafstad
157
Oslo Birth Cohort 1992-93 All birth; birth
weight>2kg, no O
2
within
6 hours of birth
No association

Uterus related complications
increased asthma risk (OR = 2.5)
Negele
162
Birth cohort,
Germany
1997-99 2500; 2-yr follow up OR recurrent wheezing 1.41
(1.02-1.96)
Prevalence: 17.4%

Juhn
15
Retrospective cohort,
USA
1976-82 7106 children 1-7yrs OR asthma 0.93 (0.6-1.4)
Cumulative incidence rates
are higher before 3 years for
CS and lower after 3 years
compared to VD
Prevalence 10%
Variable follow-up (1-7yrs) for Dx
Non-proportional hazard
assumption violated
Asthma Dx from medical records
Hakansson
163
Retrospective study,
Sweden
1984-96 1-13 yrs OR asthma 1.31 (1.23-1.40) No difference between elective
and emergency CS
Prevalence: 6.5%
Bernsen
164
Retrospective cohort,
Netherlands
1988-90 1961 children from 700
families
OR asthma by 6: 1.03 (0.51-
2.08)
Prevalence 4% with 13% missing
data on mode of delivery

104
Table 4.3, Continued.

Author Study design Birth
year
Subjects Findings Comments
Renz-Polster
165
Retrospective
cohort, USA
1990-92 7872 children 3-
10yrs
OR asthma 1.24 (1.01-1.53) Effects stronger in girls (P =
0.009)
OR NS in boys
Annesi-
Maesano
150

Cross-sectional 1973-90 4,065 children
between 1 and 18 yrs
of age
OR
ever
= 1.20 (NS) Threatened miscarriage (OR = 4.8)
and fetal malposition increased
asthma risk (OR = 3.6)
Rusconi
117
Cross-sectional
(SIDRIA)
1995-96 15,609 6-7 years old OR early transient wheezing: 104
(0.90-1.20)
OR for persistent wheezing: 1.12
(0.93-1.36)
OR for late onset wheezing: 0.99
(0.83-1.19)

McKeever
116
General Practice
Research
Database, West
Midlands, UK
- 24,690 children
between 0-11 yrs
(median follow up
2.9 yrs)
No association Mean age of asthma onset was 1.6
yrs, 21% asthma prevalence, CS
prevalence was 17%
Abbreviations:

APGAR, Activity Pulse Grimace Appearance Respiration at birth; CS, caesarean section delivery; EBF, exclusive breast-feeding; IgE, immunoglobulin E;
NS, not significant; OR, odds ratio; RI, respiratory infections; SPT+, skin prick testing positivity; VD, vaginal delivery;

105
4.4.2 Other Birth Related Factors
Some studies found that instrument assisted delivery (vacuum extraction and forceps
delivery) increased asthma risk,
16, 163
whereas others did not find significant
associations.
164
Induction of labor was marginally associated with asthma in few
studies.
15, 164
In one study, long labor were associated with increased asthma risk and
multiple gestation was associated with reduced risk of asthma.
16
However, the results
are not adjusted for maternal factors such asthma, obesity and age, which has been
associated with pregnancy and/or labor complications.
166-174

4.5 Summary and Conclusions
Review of data from observational epidemiologic studies provides evidence that both
maternal reproductive factors and prenatal exposures and experiences could play
important roles in asthma occurrence in children. However, heterogeneity of study
population, use of different definition of asthma based on follow-up time, lack of data
on age at asthma onset and other confounding variables, and geographical variation in
obstetric and neonatal/pediatric cares often makes it somewhat difficult to compare
findings across studies.

Notwithstanding these methodological difficulties and inconsistencies of findings
across studies, maternal factors such as asthma, and smoking and diet during
pregnancy appear to have strong associations with asthma development in early
childhood. In addition, maternal exposures to infections, endotoxin and allergen may

106
act independently or could have complex biological interactions that may affect
immune development and differential gene expression during fetal and early postnatal
life. Although the effect of early postnatal exposures to endotoxin or farm exposures
have been associated with reduced asthma risk, whether prenatal exposures to these
exposures as opposed to later in childhood could have differential impact on asthma
risk in offspring remains to examined in detail.

Among the dietary factors, associations between antioxidant vitamins and
consumption of fish rich in omega-3 fatty acids appear to beneficial effects on asthma
occurrence. Maternal fish intake during pregnancy has the potential to influence
immune development in the fetus.
175
Although randomized clinical trials conducted in
children did not find any association between fish-oil supplementation (sources of
omega-3 fats) and asthma,
101
in the Avon Longitudinal Study of Parents and Children
(ALSPAC) study, linoleic acid: α-linolenic acid ratio was associated with increased
risk of late onset wheeze.
98
Because not all fish are rich in omega-3 fatty acids, and
commercially available fish-sticks are poor source of omega-3 fats and a source of
deleterious trans-fatty acids, it will be important to simultaneously examine the role of
maternal intakes of oily-fish and fish-stick during pregnancy and asthma occurrence in
children. Whether such associations vary by susceptibility factors (e.g., parental
asthma, gestational age, etc.) and by asthma phenotypes could also provide useful
information to identify the susceptible population.

107
Although studies have examined the impact of Cesarean section delivery on childhood
onset asthma, further research is warranted to examine whether such risk varies by
asthma phenotypes. Because maternal asthma and preterm birth have been positively
associated with C-section and the prevalence of C-section has increased significantly
over the last several decades (indicating change in indications for and management of
C-section birth), it is important to determine whether the association between C-
section delivery and childhood onset asthma could also vary by maternal asthma and
by calendar period of birth among children who were born at term.

Although not discussed in this review, an accumulating body of evidence also
indicates that both lifestyle and environmental factors may play important roles in
asthma development. Children could be exposed to sources of allergens (cockroach),
endotoxin (pets, farm animals), chemicals (pesticide and herbicide), and to sources of
infections (from siblings and in day care centers) after birth. Because of children’s
hand-to-mouth behavior, closeness to the playground, low ratio of skin surface to body
mass and reduced ability to detoxify toxic substances, it could be hypothesized that
timing of such exposures have differential impact on allergic sensitization and asthma
occurrence. Therefore, further study that evaluates the impact of these exposures by
age at exposure and by asthma phenotype could identify the differential impact of
timing of exposures on different asthma phenotypes.

108
Finally, identification of the factors that could lead to prevent asthma occurrence is the
overreaching goal of epidemiologic studies. For early childhood asthma, review of the
existing literature strongly suggests that in utero and early postnatal life provide the
critical window where exposures and events could affect asthma risk in general or that
of particular asthma phenotype. Emerging evidence also suggest that genetic
susceptibilities could modulate such associations. Knowledge of asthma phenotype-
specific risk factors could be utilized to formulate tailored intervention strategies,
which will be better suited in preventing asthma development in young children.
Given the enormous burden from childhood asthma, further research is needed to
assess the role of these exposures in relation to genetic susceptibilities during critical
windows of development.

109
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125
Chapter 5: Maternal Fish Consumption during Pregnancy and Risk of Early
Childhood Asthma (Manuscript 1)

Chapter 5 Abstract
Maternal fish consumption during pregnancy may affect children’s asthma risk by
modulating early-life immune development. Type of fish intake may be important
because of differences in fatty acid content. To test this hypothesis, we conducted a
nested case-control study, selecting subjects from the Children’s Health Study, a
population-based study of school-aged children in southern California. Cases had
physician-diagnosed asthma and controls were asthma-free by age 5 years. Mothers or
guardians provided information on fish consumption during pregnancy in telephone
interviews. We computed odds ratio (OR) and 95% confidence interval (CI) by using
conditional logistic regression models that accounted for the sampling. In children
born to mothers with a history of asthma, the OR of asthma was 0.20 (95% CI = 0.06–
0.65) when mothers ate oily fish at least monthly during pregnancy compared with no
consumption (p
trend
= 0.006). Maternal oily fish consumption during pregnancy did not
benefit children of non-asthmatic mothers. In contrast, fish stick (a source of trans-
fats) consumption during pregnancy increased asthma risk in children (OR = 2.04;
95% CI = 1.18–3.51). Our results suggest that maternal oily fish intake during
pregnancy may protect offspring from asthma; however, eating fish sticks during
pregnancy may increase asthma risk in children.

126
5.1 Introduction
Maternal exposures during pregnancy are important in fetal and postnatal immune
development,
1-4
lung growth,
5, 6
and subsequent asthma occurrence in offspring.
7

Maternal diet, especially fish intake may be associated with chronic inflammatory
diseases such as asthma because the n-3 polyunsaturated fatty acids (n-3 PUFAs) in
oily fish have anti-inflammatory properties.
2
Studies have shown that cord blood of
neonates born to mothers who had fish oil supplementation during pregnancy had
significantly higher concentrations of n-3 PUFAs in the form of eicosapentaenoic acid
(EPA) and docosahexaenoic acid (DHA) in their red blood cells and significantly
lower interleukin-13 (IL-13) and thromboxane A
2
levels in plasma.
2, 3
In a recent
randomized clinical trial, allergy was significantly less common in infants born to
mothers who received fish oil during pregnancy than those born to mothers receiving
placebo.
4
Although studies of fish oil supplementation or fish intake in early childhood
have reported inconsistent results for asthma symptoms in children,
8-10
the potential
role of maternal fish intake during pregnancy on early life asthma occurrence has not
been examined.

The type of fish in the diet may also be an important factor. Fatty acid composition
differs between oily fish and commercially prepared fish sticks. Oily fish, such as
mackerel and salmon, contains large amounts of n-3 PUFAs mainly in the form of
EPA and DHA.
11
Omega-3 PUFAs have important anti-inflammatory properties
because they compete with endogenous ligands for both the cyclooxygenase (COX)

127
and the lipoxygenase (LOX) enzymes and decrease the synthesis of arachidonic acid
(AA) derived inflammatory mediators, namely, prostaglandin E
2
(PGE
2
) and
leukotriene B
4
(LTB
4
).
11
In addition, n-3 PUFAs decrease AA content in cell
membranes, COX-2 and 5-LOX expression, lymphocyte proliferation, and cytokine-
induced adhesion molecule expression (e.g., ICAM-1, VCAM-1, and E-selectin).
11, 12

In the presence of PGE
2
, synthesis of T
H
2 cytokines (e.g., IL-4, IL-5, and IL-10) is
increased and synthesis of the T
H
1 cytokines (e.g., IL-2, and IFN- γ) is decreased.
13-15

By suppressing PGE
2
synthesis, n-3 PUFAs present in oily fish favors T
H
1 over T
H
2-
mediated immunity and, thereby, may reduce asthma risk.

In contrast, fish sticks, which are long fillets of fish that are breaded and/or battered,
only have between 40% and 72% of fish flesh by weight in the United States. Usually
fish belonging to the Gadidae family (e.g., cod and Atlantic pollock) are used. Fish in
this family are poor sources of n-3 PUFAs.
16
Moreover, the oils (corn, canola,
cottonseed, and soybean) used in the preparation of fish sticks contain relatively high
concentration of n-6 PUFAs. Although the n-3 PUFA content is relatively high in
canola and soybean oils compared with the trace amounts present in corn and
cottonseed oils, heating all these oils results in the formation of trans-unsaturated fatty
acids or trans-fats. In a randomized clinical trial, subjects on “stick” margarine diet
containing high levels of trans-fats had significantly higher levels of IL-6 and TNF- α
than those on soybean oil diet,
17
and in an ecological study, intake of trans-fat

128
predominantly from hydrogenated vegetable fat was positively associated with
childhood asthma prevalence in 10 European countries.
18

On the basis of these findings, we hypothesized that maternal fish intake during
pregnancy influences asthma occurrence in the offspring during their early childhood
and that type of fish intake (oily fish vs. fish sticks) has opposing role in such disease
occurrence. To evaluate these hypotheses, we conducted a case-control study nested in
the Children’s Health Study (CHS), a population-based study of respiratory health in
school-aged children residing in southern California.

5.2 Materials and Methods
5.2.1 Study Design and Subjects
Subjects were part of the CHS and details of the CHS and this nested case-control
study have been described previously.
19, 20
In brief, subjects in the CHS cohort were
fourth, seventh, and tenth grade students in 1993 and fourth grade students in 1995
who attended public school classrooms in 12 southern California communities. At
study entry, parents or guardians of each participating student provided written
informed consent and completed a self-administered questionnaire, which included
detailed information about demographic and household characteristics, the child’s
family and respiratory health history, and exposure to environmental factors that might
contribute to asthma.

129
For this nested case-control study, we used a countermatching design based on
exposure to maternal smoking.
22
We selected all children from the CHS who had
asthma diagnosis by age 5 years (n = 338). Controls were asthma-free by age 5 years
and were randomly selected from 1 of 96 matching strata (i.e., 4 grades, 2 genders,
and 12 communities) and were countermatched to cases on in utero exposure to
maternal smoking. Between December 1999 and December 2001, we recruited 279
cases (82.5%) and 412 controls (72.3%). We interviewed the biological mother for
most of the study subjects (i.e., 95.3% of the cases and 90.3% of the controls). In the
absence of biological mother, we interviewed the biological father, stepmother, or the
legal guardian. The mothers of the remaining children either declined an interview or
could not be contacted. Therefore, our final sample consisted of 691 subjects with 279
cases and 412 controls. The University of Southern California Institutional Review
Board approved the study. All subjects gave informed consent.

5.2.2 Exposure Assessment
Maternal intake of fish during the index pregnancy was collected for four categories of
fish:
• Oily fish containing > 2% fat, which included blue mackerel, Atlantic salmon, southern
blue-fin tuna, blue-eye cod, rainbow trout, mullet, blue grenadier, tailor, silver bream,
gemfish, blackfish, orange roughy, pilchards, redfish, yellowtail, and tarwhine,
• Non-oily fish containing ≤2% fat, which included flounder and shark,

130
• Fish sticks that were commercially prepared, frozen boneless white fish, crumbled
and fried in oil, and
• Canned fish (e.g., tuna, salmon, and sardines).
In the questionnaire, the frequency of maternal fish intake during pregnancy was
grouped into five categories: never, rarely (i.e., less than once a month), monthly,
weekly, and daily. However, because few mothers ate fish on a daily or weekly basis,
we combined daily, weekly, and monthly intake into one category labeled as “at least
monthly.”

5.2.3 Outcome Assessment
Asthma status was assigned by parental report of physician-diagnosed asthma from the
baseline questionnaire collected at the cohort entry. We classified the asthma cases
into three groups: early transient asthma, early persistent asthma, and late-onset
asthma. Early transient asthma cases were diagnosed before age 3 years, but they did
not have any asthma symptoms or medication use in the previous 12 months or after
first grade. Early persistent asthma was defined as diagnosis of asthma before age 3
years and at least one episode of asthma or wheeze or asthma medication use in the 12
months before study entry or after starting first grade. Subjects diagnosed with asthma
after age 3 years were classified as having late-onset asthma. Of the 279 cases, 47 had
early transient asthma (16.8%), 166 had early persistent asthma (59.5%) and 66 had
late-onset asthma (23.7%).

131
5.2.4 Statistical Analysis
We computed the odds ratios (ORs) and 95% confidence intervals (CIs) for physician-
diagnosed asthma by fitting conditional likelihood logistic regression models that
accounted for the countermatched sampling following the methods described by
Langholz and Goldstein.
22
We used missing indicator variables for unavailable data on
maternal fish intake and other covariates.
23
Nonparticipation, for reasons including
refusal to participate or could not be contacted, were treated as Bernoulli trial events
and were factored into the countermatched likelihood by using a “two-stage” sampling
approach. We computed sampling weights for each stratum based on the numbers of
subjects with or without exposure to any maternal smoking in utero and used these
sampling weights into the conditional logistic regression likelihood to compute
unbiased risk estimates. Although there was a limited number of cases with early
transient and late-onset asthma, we assessed the role of the exposures in different
subgroups of asthma by using pairwise conditional logistic regression. We assessed
confounding by fitting models that included both the fish intake variable and each
potential confounder individually. Any covariate that resulted in a 10% change in the
parameter estimate was considered a potential confounder. Furthermore, effect
modification by these factors was assessed by using a likelihood ratio test by adding
an interaction term to the main effects model in the usual way.
24
All tests were two-
sided at a 5% significance level. Data were analyzed with the statistical software
package SAS (version 8.2; SAS Institute Inc, Cary, NC).

132
5.3 Results
Most of the children were non-Hispanic white (62.2%) or male (59.5%) (Table 5.1).
Annual family income, for most children, ranged between $30,000 and $100,000.
Children’s asthma risk was increased in children with a history of maternal asthma,
maternal smoking during pregnancy, and prematurity and was reduced with number of
siblings and maternal age.

Maternal fish intake during pregnancy was associated with asthma risk in the children
(Table 5.2). Maternal oily fish consumption at least monthly was protective for
persistent asthma in the children (OR = 0.45; 95%CI = 0.23–0.91). Commercially
prepared fish stick consumption during pregnancy, however, was associated with
increased asthma risk across all asthma subtypes. Compared with children whose
mothers did not eat fish sticks during pregnancy, children born to mothers who ate fish
sticks at least monthly during pregnancy had a two-fold higher risk of asthma
(OR = 2.04; 95%CI = 1.18–3.51) and had a significantly increasing trend in asthma
risk with increasing maternal intake of fish sticks during pregnancy (p
trend
= 0.01).

133
Table 5.1. Selected characteristics of the case-control study participants.
Case
a

N (%)
Controls
a

N (cohort %)
b

OR
c
(95% CI)
Gender
Male 177 (63.4) 234 (52.3) Matched
Female 102 (36.6) 178 (47.7)
Race/Ethnicity
Non-Hispanic White 164 (58.8) 266 (57.7) 1
Hispanic White 66 (23.7) 89 (30.0) 0.91 (0.57-1.44)
African-American 13 (4.6) 22 (3.6) 1.31 (0.54-3.17)
Asian and others 36 (12.9) 35 (8.7) 1.49 (0.78-2.83)
Annual family income (U.S. dollars)
≤ $14,999 37 (14.8) 86 (17.6) 1
$15,000 – $29,999 40 (16.0) 59 (20.1) 1.55 (0.79-3.04)
$30,000 – $49,999 58 (23.0) 98 (27.4) 1.38 (0.74-2.57)
$50,000 – $99,999 99 (39.4) 102 (27.8) 1.87 (1.02-3.43)
≥ $100,000 17 (6.8) 20 (7.5) 0.67 (0.26-1.70)
Maternal age at child’s birth (years)
<25 118 (43.5) 204 (46.9) 1
25-34 148 (54.6) 168 (45.3) 1.29 (0.88-1.90)
≥ 35 5 (1.9) 23 (5.8) 0.19 (0.05-0.65)
Maternal education
< 12
th
grade 14 (11.3) 46 (10.4) 1
12
th
grade 80 (37.7) 154 (36.1) 1.84 (0.86-3.93)
Some college 122 (36.8) 150 (36.3) 2.68 (1.27-5.67)
College 27 (7.1) 29 (8.4) 1.87 (0.74-4.73)
Some graduate 32 (7.1) 29 (8.8) 1.89 (0.75-4.78)
Maternal history of asthma
No 200 (72.7) 347 (84.8) 1
Yes 75 (27.3) 61 (15.2) 2.42 (1.51-3.87)
In utero exposure to maternal smoking
No 211 (75.6) 149 (81.6) 1
Yes 68 (24.4) 263 (18.4) 1.56 (1.14-2.14)
Gestational age
Term birth 227 (81.9) 363 (92.6) 1
<4 week premature 24 (8.7) 28 (5.1) 1.88 (0.95-3.71)
≥4 week premature 26 (9.4) 13 (2.3) 2.71 (1.20-6.15)
Exclusive breast-feeding for 4 months
No 163 (59.5) 280 (63.9) 1
Yes 111 (40.5) 121 (36.1) 1.12 (0.75-1.67)
Health insurance coverage
No 26 (9.4) 62 (17.0) 1
Yes 250 (90.6) 346 (83.0) 1.69 (0.95-3.01)
Number of siblings
0 22 (7.9) 34 (7.6) 1
1 110 (39.4) 119 (25.3) 0.67 (0.42-1.07)
2 87 (31.2) 132 (31.0) 0.66 (0.37-1.17)
3 39 (14.0) 75 (18.9) 0.31 (0.16-0.62)
>3 21 (7.5) 52 (17.2) 0.58 (0.28-1.22)
a
Numbers do not always add up to the total number of cases and controls because of missing data.

b
Number of controls in the case-control study (predicted percent distribution in the Children’s Health
Study cohort).

c
OR,

Univariate matched odds ratio; CI, confidence interval.

134
Table 5.2. Associations between maternal oily-fish and fish-stick consumption during pregnancy
and child’s risk of any, early transient, early persistent and late-onset asthma.
Any asthma Early transient
asthma
Early persistent
asthma
Late-onset
asthma
OR

a
95% CI OR
b
95% CI OR

a
95% CI OR

a
95% CI
Maternal oily-fish consumption during pregnancy

Never 1 - 1 - 1 - 1 -
Rarely 1.01 0.54-1.89 0.68 0.17-2.67 1.07 0.53-2.17 0.80 0.26-3.09
At least monthly 0.80 0.47-1.36 0.99 0.34-2.87 0.45 0.23-0.91 0.84 0.33-2.12
p
trend
0.40 0.92 0.04 0.66

Maternal fish-stick consumption during pregnancy

Never 1 - 1 - 1 - 1 -
Rarely 1.15 0.66-2.01 0.74 0.24-2.27 1.51 0.75-3.04 0.98 0.34-2.89
At least monthly 2.04 1.18-3.51 2.26 0.67-7.58 2.46 1.26-4.80 3.05 1.04-8.93
p
trend
0.01 0.30 0.01 0.07
a
OR,

odds ratio; CI, confidence interval. ORs adjusted for maternal asthma, race/ethnicity, maternal age, maternal
education, gestational age, number of siblings, exclusive breast-feeding, and mutually adjusted for the other fish
variable in the table.

b
ORs adjusted for maternal asthma, race/ethnicity, gestational age, number of siblings, exclusive breast-feeding,
and mutually adjusted for the other fish variable in the table.

The association between maternal oily fish intake and child’s risk of developing
asthma was larger in children whose mothers had asthma compared with children with
asthma-free mothers (p
interaction
= 0.02; Table 5.3). In children born to mothers with
asthma, maternal intake of oily fish rarely or at least monthly during pregnancy was
associated with odds ratios of 0.45 (i.e., 1.78/3.97; 95%CI = 0.13–1.59) and 0.20 (i.e.,
0.81/3.97; 95%CI = 0.06–0.65) for childhood asthma, respectively (p
trend
= 0.006).

The associations of oily fish intake were strongest for early persistent and late-onset
asthma. In contrast, children of asthma-free mothers had no benefit from maternal
consumption of oily fish during pregnancy. Maternal history of asthma did not

135
significantly modify the association between maternal fish stick consumption and
childhood asthma.

We did not observe any statistically significant association between maternal non-oily
fish or canned fish consumption during pregnancy and asthma risk in the offspring
(data not shown). Paternal history of asthma, maternal smoking during pregnancy,
second-hand tobacco exposure, and yearly family income did not confound or modify
the associations between different maternal fish intakes and childhood asthma
outcomes. Therefore, we did not include these variables in the final regression models.
Gestational age, maternal age, maternal education, and race did not modify the
observed associations.

136
Table 5.3. Joint effects of maternal asthma and maternal oily-fish consumption during pregnancy on children’s asthma risk.
Maternal
asthma
Maternal oily-fish
consumption
during pregnancy
Any asthma Early transient
asthma
Early persistent
asthma
Late-onset asthma
OR

b
95% CI OR
c
95% CI OR

b
95% CI OR

b
95% CI
No Never 1.00 1.00 1.00 1.00
No Rarely 1.31 0.65-2.67 0.70 0.16-3.11 1.55 0.68-3.52 0.84 0.19-3.71
No At least monthly 1.09 0.61-1.94 1.38 0.42-4.61 0.62 0.29-1.31 1.43 0.51-3.99
p-trend 0.70 0.67 0.35 0.42

Yes Never 3.97 2.07-7.63 3.89 0.83-18.18 5.58 2.52-12.33 6.47 1.92-21.81
Yes Rarely 1.78 0.54-5.90 1.95 0.10-40.01 2.13 0.57-7.99 8.11 0.47-14.71
Yes At least monthly 0.81 0.29-2.28 0.98 0.12-7.82 0.63 0.16-2.56 0.33 0.04-2.76

p-trend 0.006 0.31 0.006 0.01

p-interaction 0.02 0.50 0.06 0.01
a
OR,

odds ratios; CI, confidence interval.

b
ORs adjusted for maternal asthma, race/ethnicity, maternal age, maternal education, gestational age, number of siblings, exclusive
breast-feeding, and maternal fish-stick consumption during pregnancy.

c
ORs adjusted for maternal asthma, race/ethnicity, gestational age, number of siblings, exclusive breast-feeding, and maternal fish-stick
consumption during pregnancy.

137
5.4 Discussion
Maternal fish intake during pregnancy influenced childhood asthma occurrence.
Overall, children were at reduced asthma risk when their mothers ate oily fish, and
they were at increased asthma risk when their mothers consumed fish sticks during
pregnancy. However, the data showed that risk reduction in early persistent and late-
onset asthma with maternal oily fish intake during pregnancy was mainly in children
whose mothers had a history of asthma. Moreover, we observed a statistically
significant decreasing trend in asthma risk in the children of asthmatic mothers with
increasing frequency of maternal oily fish intake during pregnancy. In contrast,
consumption of commercially prepared fish sticks during pregnancy increased asthma
risk in children.

To our knowledge, our finding of a protective effect of oily fish intake during
pregnancy on asthma in the children of asthmatic mothers is a novel one. Asthmatic
mothers, by eating oily fish during pregnancy, may have reduced their children’s cell
membrane proinflammatory lipid mediators, thus reducing asthma risk in their
children. Moreover, maternal oily fish intake may interact with asthma susceptibility
genes during fetal life, which may reduce asthma risk in childhood. In addition, it is
plausible that oily fish intake by asthmatic mothers may reduce their own disease
severity during pregnancy, which may lower the probability of premature birth and
low neonatal birth weight; the latter two factors are associated with increased asthma

138
risk in the children.
25
Eating oily fish or fish oil supplementation during lactating
periods significantly increases breast milk n-3 PUFA concentrations.
26, 27
Although we
did not ask the mothers about their fish consumption after childbirth, it is likely that
they did not change their dietary habits. If so, breast milk could be a continuous source
of n-3 PUFAs for the neonate, imparting protection against asthma development in
early life. The finding that paternal asthma had no significant role on the association
between maternal oily fish consumption during pregnancy and early life asthma gives
some support to our hypothesis that maternal fish consumption influences fetal
immune development and modulates inflammatory processes in mothers with a history
of asthma.

Lower concentration of n-3 PUFAs, together with the presence of high levels of trans-
fats from hydrogenated vegetable oil in fish sticks, may have resulted in the increased
asthma risk that we observed in this study. Many other processed food products
consumed by pregnant women may contain trans-fats. A more complete assessment of
dietary intake of trans-fats and fish sticks during pregnancy is needed to examine their
role in childhood asthma.

One limitation of our study is that assessment of dietary intake of fish involved
retrospective recall of exposures, making misclassification of intake a concern. A
number of methodological studies suggest that recall of usual diet during past
pregnancies is reliable. Recall of dietary intake during a previous pregnancy 3–7 years

139
before the interview was similar to the recall of current intakes.
28
Another study
showed that subjects recalled their present and 10- to 15-years earlier dietary intakes
with almost equal reliability when personal interview was conducted by using a
questionnaire.
29
Based on these studies, the reliability of longer-term recall of maternal
diet during pregnancy is similar to recall over a short period of time. We also observed
opposite directions in the relative risk estimates for oily fish and fish stick
consumption for childhood asthma, suggesting that the recall of fish intake was not
systematically different in cases and controls. On the basis of these considerations, it is
unlikely that mothers who were asthmatic or whose children had asthma would report
types of fish intake differently from non-asthmatics. Thus, although nondifferential
misclassification in exposure assessment is likely, which would reduce our risk
estimates toward the null, a systematic bias that would account for our results is
unlikely.

Another limitation is that other consumed food products may have contained trans-
fats, but we did not collect information about any sources of trans-fats beyond fish
sticks. We also did not collect a full dietary history because our a priori hypothesis
focused on fish intake during pregnancy. Although EPA and DHA are found
exclusively from oily fish, alpha-linolenic acid (ALA) from plant sources, such as nuts
(especially English walnut), flaxseed, and soybean or their oils, can be converted into
EPA and DHA by metabolic processes.
30
However, the metabolic conversion of ALA
into EPA and DHA is slowed significantly in the presence of diet containing higher

140
levels of n-6 PUFAs.
31
Although we did not collect information about the botanical
sources of ALA in our study, given the presence of higher level of n-6 PUFAs and low
use of flaxseed, flaxseed oil and fish-oil supplements in U.S. diet, botanical foods may
not be a significant source of EPA and DHA.
30
We recognize that fish consumption
practices may be related to other nutritional and social factors. Although we have
adjusted for social factors (i.e., race, maternal education, and family income) in our
analysis, there may be unmeasured differences in other dietary intakes that need
further investigation. However, because our risk estimates are relatively large and
there is no report of any strong dietary determinant of asthma to date, these
unmeasured dietary factors may not be significant confounders that could provide an
alternate explanation for our findings. Because few mothers ate fish on a daily or
weekly basis and we did not have information on servings consumed during such
periods, we were unable to determine the frequency or servings of oily fish intake
required to provide significant risk reduction in childhood asthma occurrence.

Childhood asthma status was determined on the basis of parental report of physician-
diagnosed asthma at cohort entry several years before any interview was conducted for
the nested case-control study. We reduced the period of recall and the associated
misclassification of asthma status by using the earlier report. The use of physician
diagnosis of asthma has been widely used in epidemiological studies, and the parental-
report reflects physician diagnosis accurately.
32, 33
A major concern in using physician-
diagnosed asthma is the under-ascertainment of asthma. Limited access to care may

141
also lead to under-diagnosis of asthma. To assess this potential source of
misclassification of outcome, we considered the effects of family income, education,
and health insurance on the risk estimates and found little change in the adjusted risk
estimates. Cases and controls were also matched on community of residence, reducing
bias from community differences in medical practice and access to care. There is also
concern that early transient wheezing may be misdiagnosed as asthma. To assess this
concern, we examined association in early transient, early persistent, and late-onset
cases and found associations in the early persistent and late-onset groups. Based on
these considerations, misclassification of asthma status is not likely to completely
explain the associations we observed.

To summarize, our results suggest that oily fish in the maternal diet during pregnancy
reduces the risk of asthma in early childhood. Maternal consumption of commercially
prepared fish sticks may place a child at higher risk for developing asthma, but further
research is needed to confirm our finding.

142
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22. Langholz B, Goldstein L. Conditional logistic analysis of case-control studies
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23. Huberman M, Langholz B. Application of the missing-indicator method in
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145
Chapter 6: Mode of Delivery Is Associated With Asthma and Allergy
Occurrences in Children (Manuscript 2)

Chapter 6 Abstract
Purpose: A growing body of evidence indicates that perinatal factors modulate
immune development and thereby may affect childhood asthma risk. In this study, we
examined the associations between birth by cesarean section (C-section) and atopic
disease occurrence in childhood.
Methods: Subjects were born in California between 1975 and 1987 and were 8 to 17
years old during their enrollment in the Children's Health Study. Our analysis was
restricted to 3464 children born at or after 37 weeks of gestation with a birth weight of
2500 g or greater based on birth certificate data. Information about sociodemographic
factors, reported physician-diagnosed asthma, and other atopic diseases was obtained
by using a self-administered structured questionnaire. Logistic regression models were
fitted to compute odds ratios (ORs) and 95% confidence intervals (CIs).
Results: Children born by C-section were at increased risk for asthma (OR, 1.33; 95%
CI, 1.01–1.75), hay fever (OR, 1.57; 95% CI, 1.24–1.99), and allergy (OR, 1.26; 95%
CI, 1.03–1.53) compared with those born vaginally. Risk associated with C-section
was the same for children regardless of family history of asthma or allergy.
Conclusion: We conclude that birth by C-section or processes associated with it may
increase the risk for atopic disease in childhood.

146
6.1 Introduction
Asthma is the most common chronic childhood disease, and understanding its cause is
a major research goal.
1
Studies have suggested that in utero and early infancy are
critical windows during which events and exposures may affect risk for atopic
diseases in childhood.
2, 3
A parallel increase in prevalences of atopic diseases and
cesarean section (C-section) delivery in developed nations has prompted several
epidemiologic studies to examine the role of C-section in the cause of atopic diseases.

Limited evidence indicates that mode of delivery may affect asthma and allergy
outcomes in children. Although some researchers observed positive associations
between C-section delivery and asthma and allergy risk in children.
4-8
, Nafstad et al.
9

did not observe an association. These investigators
9
excluded children who required
oxygen during the first 6 hours of life. Pregnancy or labor complications may lead to
C-section. By excluding children requiring oxygen in the first few hours of life, the
investigators may have excluded more children who were born by C-section than by
vaginal delivery. This may have resulted in attenuation of risk estimates. In addition,
follow-up time for these children was less (e.g., 4 years), and it may not have
adequately covered the at-risk period for developing atopic disease.

To further investigate the role of mode of delivery on asthma and allergic outcomes
during childhood, we examined the association of delivery by C-section on the
development of childhood atopic diseases within the uniquely large and diverse

147
population of children born in California and who participated in the Children's Health
Study (CHS).

6.2 Methods
The study population and methods for the CHS have been described previously,
10, 11

and a number of respiratory health associations with outdoor air pollution have been
reported.
12-17
In brief, 6259 subjects were enrolled in 1993 and 1996 from 12 southern
California communities and tracked annually by lung-function testing, self-
administered medical history and residential characteristics questionnaires, and
monitoring of school absences to assess respiratory health development and its
potential association with a number of ambient air pollutants (which were monitored
continuously in all communities for the 10-year study duration). Of children recruited
into the CHS cohort, 5013 children (80.1%) were born between 1975 and 1987 in the
state of California, 702 children were born outside California (11.2%), and the
remaining 544 children (8.7%) did not provide sufficient information to reliably
determine place of birth. For participants born in California, 4842 birth certificates
(96.6%) were obtained from the California Department of Health Services' Birth
Statistical Master Files and Birth Cohort Files.

Because low birth weight and preterm birth may influence associations between C-
section and atopic diseases, we excluded 688 children who were born before 37 weeks
of gestation and/or who weighed less than 2500 g at birth, documented by birth

148
certificate data. Subjects with missing covariate information also were excluded from
analysis, resulting in a study sample size of 3464 children. The University of Southern
California Institutional Review Board approved the study. At study entry, the child's
parent or legal guardian provided informed consent.

Detailed information on demographic characteristics and socioeconomic status (SES)
was obtained at the time of CHS enrollment. Information on mode of delivery,
maternal age at childbirth, birth weight, and birth order of the index child was
obtained from birth certificates. Parents or guardians also provided information
regarding subjects' history of hay fever, allergy, pneumonia, bronchitis, bronchiolitis,
and croup. To assess subject's allergic status, we asked each parent or guardian
whether his or her child was allergic to foods or drugs, any inhalant, or dermal
allergens other than poison ivy or poison oak.

Asthma status was determined based on parental report of physician-diagnosed
asthma. Based on the age of asthma onset and persistence patterns, we divided
subjects with asthma histories into three categories: early-onset transient, early-onset
persistent, and late-onset persistent asthma. Children with early-onset asthma were
diagnosed by the age of 3 years, and those with late-onset asthma were diagnosed after
the age of 3 years. Children with persistent asthma had wheeze and/or used asthma
medications (i.e., inhaled medications and/or corticosteroid pills or injections) in the

149
12 months before study entry. Those with transient asthma had no wheeze and had not
used asthma medications in the 12 months before study entry.

We computed odds ratios (ORs) and 95% confidence intervals (95% CIs) for
associations between mode of delivery and various respiratory outcomes by using
logistic regression. Children with missing data for a specific disease outcome were
excluded from analyses for that particular outcome. Potential confounding covariates
were included in multivariate models. We considered that calendar period of birth may
capture changes in indications and management of C-section and examined whether
the association between C-section and atopic diseases was modified by calendar
period of birth. We also tested for effect modification by maternal, paternal, and
parental history of asthma and allergy; maternal smoking during pregnancy; birth
weight; and birth order of the index child by using likelihood ratio tests. Pairwise
logistic regression was used to assess the role of mode of delivery among the three
different asthma subgroups and reported allergies (i.e., to food, drug, inhalants, or
dermal exposure). Inference of statistical significance was based on two-sided
distributions using a 5% significance level. A commercially available statistical
software package (SAS; version 8.2; SAS Institute, Inc., Cary, NC) was used for all
analyses.

150
6.3 Results
Most of the children were middle-class non-Hispanic or Hispanic white, based on
annual family income, parent or guardian education level, and health insurance
coverage at the time of CHS enrollment (Table 6.1). The majority of mothers were
older than 20 years at the time of delivery of the index child, and 18.8% smoked
during pregnancy.

Table 6.1. Selected characteristics of the study participants from the Children’s Health Study
born at term in California between 1975 and 1987.
N
a
(%) N
a
(%)
Age (years) Maternal asthma 476 (11.8)
8-9 2131 (51.3) Maternal allergy 1317 (32.9)
10-11 864 (20.8) Paternal asthma 343 (8.8)
12-13 645 (15.5) Paternal allergy 1056 (27.9)
≥ 14 514 (12.4) Maternal smoking during pregnancy 764 (18.8)
Race Secondhand smoke exposure 1641 (40.1)
Non-Hispanic White 2450 (59.3) Covered by health insurance 3511 (86.2)
Hispanic White 1168 (28.3) Birth by cesarean section 717 (20.7)
African-American 198 (4.8) Child kept in special care unit after birth 282 (6.9)
Asian 110 (2.7)
Other 204 (4.9) Maternal age at childbirth years)
Sex (boys) 2015 (48.5) <20 577 (13.9)
Informant’s education 21-25 1382 (33.3)
< 12th grade 510 (12.6) 26-30 1350 (32.5)
12th grade 849 (20.9) >30 845 (20.3)
Some college 1825 (45.1) Birth order
College 396 (9.8) 1 1740 (42.0)
Some graduate 470 (11.6) 2 1399 (33.8)
Annual family income ($) 3 636 (15.3)
<15,000 584 (16.6) >3 368 (8.9)
15,000 - 49,999 1480 (41.9)
≥ 50,000 1466 (41.5) Birth weight (g)
2500-2999 467 (13.5)
Season of birth 3000-3250 547 (15.8)
Winter (Jan-Mar) 1003 (24.2) 3251-3500 782 (22.6)
Spring (Apr-Jun) 1092 (26.3) 3501-3750 657 (19.0)
Summer (Jul-Sep) 1061 (25.5) 3751-4000 504 (14.5)
Fall (Oct-Dec) 998 (24.0) > 4000 507 (14.6)
a
Totals differ due to missing values.

151
Prevalence of C-section was 20.7%. Mean birth weights in children born by C-section
and vaginally were 3545 g (SD, 500.5 g) and 3509 g (SD, 458.0 g), respectively. The
difference in mean birth weights attained borderline statistical significance (p = 0.08,
independent t-test). Mean age of participants at the time of enrollment in the CHS was
10.5 years (SD, 2.2 years; range, 8 to 17 years). The proportion of children born by C-
section increased over time. Between the calendar periods 1975 to 1977, 1978 to 1980,
1981 to 1983, and 1983 to 1987, proportions of children born by C-section were
12.9%, 17.7%, 20.2%, and 25.1%, respectively (p < 0.0001).

Children born by C-section were at increased risk for physician-diagnosed asthma
(OR, 1.33; 95% CI, 1.01–1.75), hay fever (OR, 1.57; 95% CI, 1.24–1.99), and allergy
(OR, 1.26; 95% CI, 1.03–1.53; Table 6.2). Although the OR for late-onset persistent
asthma was stronger (OR, 1.48; 95% CI, 1.05–2.09), ORs for different subgroups of
asthma (early-onset transient, early-onset persistent, and late-onset persistent) were not
statistically significantly different from one another. In multivariate analysis, the OR
for inhalant allergy was 1.19 (95% CI, 0.94–1.50). Birth by C-section was associated
with other infectious respiratory diseases (e.g., pneumonia, bronchitis, bronchiolitis,
and croup) in univariate analysis (OR, 1.21; 95% CI, 1.02–1.45); however, ORs were
not statistically significant in multivariate analysis.

152
Table 6.2. Associations between mode of delivery and different respiratory and allergic outcomes
Ever asthma Early transient
asthma
Early persistent
asthma
Late-onset
persistent asthma
Hay fever Mode of delivery
Ca/Co
a
Ca/Co
a
Ca/Co
a
Ca/Co
a
Ca/Co
a

Vaginal delivery 379/2344 39/2344 134/2344 182/2344 403/2143
Cesarean section 129/584 15/584 40/584 71/584 154/510
Unadjusted OR (95% CI) 1.37 (1.10-1.70) 1.54 (0.85-2.82) 1.20 (0.83-1.73) 1.57 (1.17-2.09) 1.61 (1.30-1.98)
Adjusted
3
OR (95% CI) 1.33 (1.01-1.75) 1.81 (0.92-3.59) 1.17 (0.74-1.84) 1.48 (1.05-2.09) 1.57 (1.24-1.99)

Any allergy Food or drug
allergy
Inhalant allergy Dermal allergy Other respiratory
diseases
c

Ca/Co
a
Ca/Co
a
Ca/Co
a
Ca/Co
a
Ca/Co
a

Vaginal delivery 775/1884 232/1884 536/1884 118/1884 776/1903
Cesarean section 249/448 67/448 168/448 29/448 232/469
Unadjusted OR (95% CI) 1.35 (1.13-1.61) 1.22 (0.91-1.62) 1.32 (1.08-1.61) 1.03 (0.68-1.57) 1.21 (1.02-1.45)
Adjusted
3
OR (95% CI) 1.26 (1.03-1.53) 1.18 (0.85-1.62) 1.19 (0.94-1.50) 1.07 (0.67-1.70) 1.05 (0.87-1.27)

a
Number of subjects with/without the disease under study who were born at or after 37 weeks of gestation with birth weight of 2500 g or greater.

b
OR, odds ratio; CI, confidence interval. Adjusted for age (as a continuous variable), sex, race, birth order, birth weight, community of residence, parental
or guardian education, health insurance coverage, parental history of asthma and allergy, exposure to in utero smoking, exposure to
secondhand smoke, maternal age at childbirth, requirement for special care after birth, calendar period of birth, and history of pneumonia,
bronchitis, bronchiolitis, and croup.

c
Pneumonia, bronchitis, bronchiolitis, and croup.

153
Because there was overlap between asthma and allergy outcomes, we compared
children with asthma alone, allergy alone, or both asthma and allergy with those who
had neither asthma nor allergies. We found no substantial differences in ORs among
the three groups with asthma and/or allergy (Table 6.3).

Table 6.3. Mode of delivery on joint outcomes of asthma and allergy
Mode of delivery No asthma or
allergy
Only asthma Only allergy Both asthma
and allergy
Vaginal delivery 1735 134 534 235
Cesarean section 400 45 167 81
Unadjusted OR (95% CI) 1 1.46 (1.02-2.08) 1.36 (1.11-1.67) 1.50 (1.14-1.97)
Adjusted
a
OR (95% CI) 1 1.57 (1.03-2.41) 1.34 (1.07-1.67) 1.50 (1.02-2.20)
a
A OR, odds ratio; CI, confidence interval. ORs adjusted for age (as a continuous variable), sex, race, birth order,
birth weight, community of residence, parental or guardian education, health insurance coverage, parental history
of asthma and allergy, exposureto in utero smoking, exposure to secondhand smoke, maternal age at childbirth,
requirement for special care after birth, calendar period of birth, and history of pneumonia, bronchitis, bronchiolitis,
and croup.

In mothers with and without a history of asthma, C-section rates were 20.3% (i.e., 619
of 3056 mothers) and 24.0% (98 of 408 mothers), respectively (p = 0.08, chi-square
test). However, maternal history of asthma did not modify the associations between
birth by C-section and any of the outcomes of interest (all p ≥ 0.10). Maternal allergy,
paternal history of asthma or allergy, maternal smoking during pregnancy, birth
weight, calendar period of birth, and birth order of the index child also did not modify
any of these associations.

154
6.4 Discussion
In the present study, we observed that mode of delivery was associated with early
childhood asthma and allergy occurrences, and children born by C-section were at
increased risk for asthma, hay fever, and allergy compared with those who had a
vaginal birth. Although the mechanisms by which C-section may affect asthma,
allergy, and hay fever occurrences are not completely understood, there are several
biologically plausible mechanisms by which C-section may affect asthma, allergy, and
hay fever occurrences in children.

First, differences in immune development in early life between children born vaginally
and by C-section may be important. Intestinal bacterial flora are important in immune
development,
18
and children with atopic diseases have been found to have lower gut
levels of Bacteroides and Bifidobacterium species than children without atopic
disease.
19, 20
Bifidobacteria have probiotic properties and are associated with reduced
risk for atopic disease in children.
21
C-Section has been shown to delay and alter the
development of intestinal bacterial flora in infants.
22
This may, in turn, alter immune
development and subsequently increase the risk for atopic disease in children.

Second, women and unborn children requiring C-section are more likely to have
deliveries complicated by intrauterine infection or chorioamnionitis. Such intrauterine
exposure to microbial antigens and the associated immunologic stimulation have been
suggested to increase the risk for asthma.
23
In addition, because women requiring C-

155
section are less likely to breast-feed,
24
their children lose the protection against
childhood asthma offered by successful breast-feeding.
25
Finally, children born by C-
section do not experience the forcible removal of amniotic fluid from their lungs
during passage through the birth canal. As a result, these children are much more
likely to experience “wet lung” or transient tachypnea of the newborn.
26
Such
impaired fluid clearance may alter multiple aspects of pulmonary physiology and act
as an asthma inducer in susceptible children.
27
For the present study, we did not have
information on intrauterine infection and breast-feeding to adjust for these factors.
Therefore, we did not have data to directly assess this potential bias. However, we
conducted a sensitivity analysis to examine whether breast-feeding confounded the
observed associations by using data from a nested case–control study
3
that included a
subset of 569 subjects of this study. We observed little change in associations between
C-section and atopic diseases when we adjusted for breast-feeding. Based on these
results, it is unlikely that our results are explained by confounding by differences in
breast-feeding by mode of delivery.

Early life exposures to allergens may vary by mode of delivery, and absence or
avoidance of these factors may reduce the risk for atopic disease. Although we did not
have information about dust mites, we had information collected at baseline about the
presence of carpet, pets, and mold or mildew at home. We observed little change to
the associations between C-section and atopic diseases when we adjusted for these

156
potential confounders. In addition, associations between C-section and atopic diseases
remained similar irrespective of these exposures.

Our findings also are consistent with a number of previous studies.
4-6
Earlier studies
showed a positive association between maternal asthma and C-section.
28, 29
In our
study, we also observed greater C-section rates in mothers with a history of asthma,
but the associations between C-section and atopic diseases were not modified by
maternal history of asthma or maternal smoking during pregnancy.

Definitions of asthma and allergy in this study were based on physician-diagnosed
asthma and paternal report of allergic history, respectively. Although some researchers
recommend testing for bronchial hyperresponsiveness (BHR) to define asthma, others
have shown that such testing decreased sensitivity, and combining BHR results with
questionnaire data further decreased it.
30, 31
Based on this evidence, it does not appear
that the validity of questionnaire-based classification of asthma phenotype is improved
by testing BHR in children.
32
We used the International Study of Asthma and
Allergies in Childhood definition for asthma, one that has been used widely in
epidemiologic studies of asthma.
33
Because asthma is the most common chronic
illness in childhood, children with asthma may need to access health care more often
than their healthy peers. In this study, the majority of subjects had health insurance.
When we adjusted for health insurance status, we found little change in any of the
estimates, suggesting that health care access did not account for the observed results.

157
There may have been some misclassification in assessing the hay fever, allergy, and
respiratory infection outcomes by using our questionnaire data. However, the
misclassification is likely to be nondifferential and may have biased results toward
null.

Although we adjusted for parental education and health insurance coverage as
surrogate for subject SES and community of residence as surrogate for air pollution,
we acknowledge the possibility of residual confounding by these factors. In addition,
SES may have affected the ascertainment of physician-diagnosed asthma. Residual
confounding also is possible for the other variables used to obtain adjusted estimates,
and there may be other potential confounders that were not adjusted for in our
analysis. However, the consistent effect estimates for different outcomes provide some
support that the findings did not result from ascertainment bias, residual confounding,
or failure to adjust for other potential confounders.

In California, information on birth weight, maternal age at childbirth, and mode of
delivery obtained from birth certificates has been found to be valid and reliable, but
data on pregnancy, labor complications, and Apgar scores are less complete.
34

Because C-section was associated positively with premature birth (p = 0.08) and the
latter may result from pregnancy complications, we restricted our analysis to children
born at term ( ≥37 weeks of gestation). To address confounding by labor
complications, we inquired whether the child was kept in a special care unit at a

158
hospital after birth, and analyses were adjusted accordingly. Because we observed
good agreement between maternal recall of birth weight and birth weight information
culled from birth certificates ( κ statistic = 0.75; 95% CI, 0.71–0.80; data not shown),
maternal recall of the child's admission to a special care unit after birth was considered
relatively reliable and a potential surrogate for labor complications affecting fetal and
neonatal health.

The proportion of children born by C-section increased during the study period and
was similar to prevalence rates observed in California and in the United States.
35-38

This suggests that our sample was representative of the source population. Because
associations between C-section and atopic diseases remained similar by calendar
period of birth, these associations may not be explained completely by the change in
indications for and management of C-section birth that occurred over time. Birth
weight, maternal asthma, and maternal smoking are associated with C-section and
potentially could modify the associations between C-section and atopic disease.
Unlike previous studies, we addressed the issue of effect modification by these factors
in our study and observed that the associations remained similar regardless of birth
weight, maternal asthma, and maternal smoking.

In conclusion, our findings suggest that mode of birth may influence asthma and
allergy occurrences in children. If this is true, then increases in C-section birth rates

159
during the last several decades also may help to explain the observed increase in
asthma occurrences in children.

160
Chapter 6 References
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United States, 1960-1995. MMWR CDC Surveill Summ 1998; 47:1-27.

2. Gilliland FD, Li YF, Peters JM. Effects of maternal smoking during pregnancy
and environmental tobacco smoke on asthma and wheezing in children. Am J
Respir Crit Care Med 2001; 163:429-36.

3. Salam MT, Li YF, Langholz B, Gilliland FD. Early-life environmental risk
factors for asthma: findings from the Children's Health Study. Environ Health
Perspect 2004; 112:760-5.

4. Kero J, Gissler M, Gronlund MM, et al. Mode of delivery and asthma -- is
there a connection? Pediatr Res 2002; 52:6-11.

5. 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.

6. Eggesbo M, Botten G, Stigum H, Nafstad P, Magnus P. Is delivery by cesarean
section a risk factor for food allergy? J Allergy Clin Immunol 2003; 112:420-6.

7. McKeever TM, Lewis SA, Smith C, Hubbard R. Mode of delivery and risk of
developing allergic disease. J Allergy Clin Immunol 2002; 109:800-2.

8. Xu B, Pekkanen J, Jarvelin MR. Obstetric complications and asthma in
childhood. J Asthma 2000; 37:589-94.

9. 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.

10. Peters JM, Avol E, Navidi W, et al. A study of twelve Southern California
communities with differing levels and types of air pollution. I. Prevalence of
respiratory morbidity. Am J Respir Crit Care Med 1999; 159:760-7.

11. Peters JM, Avol E, Gauderman WJ, et al. A study of twelve Southern
California communities with differing levels and types of air pollution. II.
Effects on pulmonary function. Am J Respir Crit Care Med 1999; 159:768-75.

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12. Gilliland FD, Berhane K, Rappaport EB, et al. The effects of ambient air
pollution on school absenteeism due to respiratory illnesses. Epidemiology
2001; 12:43-54.

13. McConnell R, Berhane K, Gilliland F, et al. Prospective study of air pollution
and bronchitic symptoms in children with asthma. Am J Respir Crit Care Med
2003; 168:790-7.

14. Gauderman WJ, Avol E, Gilliland F, et al. The effect of air pollution on lung
development from 10 to 18 years of age. N Engl J Med 2004; 351:1057-67.

15. Gauderman WJ, Gilliland GF, Vora H, et al. Association between air pollution
and lung function growth in southern California children: results from a second
cohort. Am J Respir Crit Care Med 2002; 166:76-84.

16. Gauderman WJ, McConnell R, Gilliland F, et al. Association between air
pollution and lung function growth in southern California children. Am J
Respir Crit Care Med 2000; 162:1383-90.

17. Avol EL, Gauderman WJ, Tan SM, London SJ, Peters JM. Respiratory effects
of relocating to areas of differing air pollution levels. Am J Respir Crit Care
Med 2001; 164:2067-72.

18. Bjorksten B. Effects of intestinal microflora and the environment on the
development of asthma and allergy. Springer Semin Immunopathol 2004;
25:257-70.

19. Bjorksten B, Naaber P, Sepp E, Mikelsaar M. The intestinal microflora in
allergic Estonian and Swedish 2-year-old children. Clin Exp Allergy 1999;
29:342-6.

20. Kalliomaki M, Kirjavainen P, Eerola E, Kero P, Salminen S, Isolauri E.
Distinct patterns of neonatal gut microflora in infants in whom atopy was and
was not developing. J Allergy Clin Immunol 2001; 107:129-34.

21. Kalliomaki M, Salminen S, Arvilommi H, Kero P, Koskinen P, Isolauri E.
Probiotics in primary prevention of atopic disease: a randomised placebo-
controlled trial. Lancet 2001; 357:1076-9.

22. Gronlund MM, Lehtonen OP, Eerola E, Kero P. 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.

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23. McKeever TM, Lewis SA, Smith C, Hubbard R. The importance of prenatal
exposures on the development of allergic disease: a birth cohort study using
the West Midlands General Practice Database. Am J Respir Crit Care Med
2002; 166:827-32.

24. Leung GM, Lam TH, Ho LM. Breast-feeding and its relation to smoking and
mode of delivery. Obstet Gynecol 2002; 99:785-94.

25. Kull I, Almqvist C, Lilja G, Pershagen G, Wickman M. Breast-feeding reduces
the risk of asthma during the first 4 years of life. J Allergy Clin Immunol 2004;
114:755-60.

26. Levine EM, Ghai V, Barton JJ, Strom CM. Mode of delivery and risk of
respiratory diseases in newborns. Obstet Gynecol 2001; 97:439-42.

27. Schaubel D, Johansen H, Dutta M, Desmeules M, Becker A, Mao Y. Neonatal
characteristics as risk factors for preschool asthma. J Asthma 1996; 33:255-64.

28. Demissie K, Breckenridge MB, Rhoads GG. Infant and maternal outcomes in
the pregnancies of asthmatic women. Am J Respir Crit Care Med 1998;
158:1091-5.

29. Linton A, Peterson MR. Effect of preexisting chronic disease on primary
cesarean delivery rates by race for births in U.S. military hospitals, 1999-2002.
Birth 2004; 31:165-75.

30. Jenkins MA, Clarke JR, Carlin JB, et al. Validation of questionnaire and
bronchial hyperresponsiveness against respiratory physician assessment in the
diagnosis of asthma. Int J Epidemiol 1996; 25:609-16.

31. de Marco R, Cerveri I, Bugiani M, Ferrari M, Verlato G. An undetected burden
of asthma in Italy: the relationship between clinical and epidemiological
diagnosis of asthma. Eur Respir J 1998; 11:599-605.

32. Pekkanen J, Pearce N. Defining asthma in epidemiological studies. Eur Respir
J 1999; 14:951-7.

33. Worldwide variation in prevalence of symptoms of asthma, allergic
rhinoconjunctivitis, and atopic eczema: ISAAC. The International Study of
Asthma and Allergies in Childhood (ISAAC) Steering Committee. Lancet
1998; 351:1225-32.

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34. Von Behren J, Reynolds P. Birth characteristics and brain cancers in young
children. Int J Epidemiol 2003; 32:248-56.

35. Stafford RS. Recent trends in cesarean section use in California. West J Med
1990; 153:511-4.

36. Marieskind HI. Cesarean section in the United States: has it changed since
1979? Birth 1989; 16:196-202.

37. Placek PJ, Taffel SM. Trends in cesarean section rates for the United States,
1970--78. Public Health Rep 1980; 95:540-8.

38. Taffel SM, Placek PJ, Liss T. Trends in the United States cesarean section rate
and reasons for the 1980-85 rise. Am J Public Health 1987; 77:955-9.

164
Chapter 7: Early-Life Environmental Risk Factors for Asthma: Findings from
the Children's Health Study (Manuscript 3)

Chapter 7 Abstract
Early-life experiences and environmental exposures have been associated with
childhood asthma. To investigate further whether the timing of such experiences and
exposures is associated with the occurrence of asthma by 5 years of age, we conducted
a prevalence case-control study nested within the Children's Health Study, a
population-based study of > 4,000 school-aged children in 12 southern California
communities. Cases were defined as physician-diagnosed asthma by age 5, and
controls were asthma-free at study entry, frequency-matched on age, sex, and
community of residence and countermatched on in utero exposure to maternal
smoking. Telephone interviews were conducted with mothers to collect additional
exposure and asthma histories. Conditional logistic regression models were fitted to
estimate odds ratios (ORs) and 95% confidence intervals (CIs). Asthma diagnosis
before 5 years of age was associated with exposures in the first year of life to wood or
oil smoke, soot, or exhaust (OR = 1.74; 95% CI, 1.02-2.96), cockroaches (OR = 2.03;
95% CI, 1.03-4.02), herbicides (OR = 4.58; 95% CI, 1.36-15.43), pesticides (OR =
2.39; 95% CI, 1.17-4.89), and farm crops, farm dust, or farm animals (OR = 1.88;
95% CI, 1.07-3.28). The ORs for herbicide, pesticide, farm animal, and crops were
largest among children with early-onset persistent asthma. The risk of asthma
decreased with an increasing number of siblings (p
trend
= 0.01). Day care attendance

165
within the first 4 months of life was positively associated with early-onset transient
wheezing (OR = 2.42; 95% CI, 1.28-4.59). In conclusion, environmental exposures
during the first year of life are associated with childhood asthma risk.

7.1 Introduction
Asthma is the most common chronic disease among U.S. children
1
and is the leading
cause of childhood morbidity as measured by hospitalizations and school absences.
2

Although a large number of studies of asthma have been conducted, the etiology of
childhood asthma remains to be firmly established.

An accumulating body of evidence indicates that both lifestyle factors and
environmental exposures during early life may play particularly important roles in
asthma occurrence.
3
Moreover, timing of such environmental exposures during early
development may also be critically important in allergic sensitization and later asthma
development. For example, the risks for asthma development associated with exposure
to pets, cockroaches, or farming environment appear to vary by age at exposure.
Children exposed to cats in the first 2 years of life were sensitized to cat by age 4 and
were at increased risk of severe asthma in the presence of secondhand tobacco smoke.
4

Cockroach sensitization, which often occurs at a very early age in exposed children,
5

has been associated with increased risk of incident asthma.
6
In a farming environment,
children exposed to stables in the first year of life had reduced risk of asthma
compared with children who had such exposure after 1 year of age.
7
Although early

166
exposure to endotoxin from farm environment is associated with reduced childhood
asthma risk,
8
endotoxin exposures later in life may increase asthma occurrence,
especially in agricultural settings.
9

Given the emerging evidence for age-dependent effects of early-life environmental
exposures and lifestyle factors in childhood asthma etiology, we hypothesized that
environmental exposures in early childhood, especially during the first year of life, are
associated with increased occurrence of early transient wheezing and/or early
persistent asthma. We further hypothesized that early-life experiences including infant
feeding practices, greater sibship size, and day care attendance influence the risk of
early childhood asthma. To assess these hypotheses, we conducted a case-control
study of risk factors for early-life asthma that was nested in the Children's Health
Study (CHS), a population-based study of children's respiratory health in 12 southern
California communities.

7.2 Materials and Methods
7.2.1 Subject selection
Subjects for this case-control study were selected from the CHS. Details of the CHS
have been described previously.
10, 11
In brief, the CHS is a population-based study in
which 6,259 children were recruited from public school classrooms from grades 4, 7,
and 10 in 12 communities in southern California. The average classroom participation

167
rate was 82%. The parents or guardians of each participating student provided written
informed consent and completed a self-administered questionnaire.

We used a countermatched sampling design
12
to select subjects for this nested case-
control study. Our study base consisted of 4,244 of the 6,259 children, who were
between 8 and 18 years of age at the time of enrollment in the CHS and had completed
active follow-up at schools. From these 4,244 children, we selected all children with
asthma who had been diagnosed with asthma before 5 years of age (n = 338). Matched
controls were asthma-free children and were selected randomly from each of the 96
grade-, sex-, and community-specific strata based on the number of cases in each
stratum and the cases' in utero exposure to maternal smoking status. The number of
asthma-free controls (n = 570) provided approximately equal numbers of children who
were exposed or unexposed to maternal smoking within each sampling stratum.
During the study period, mothers of 82.5% cases (n = 279) and 72.3% controls (n =
412) participated; the remaining mothers could not be located or were unwilling to be
interviewed. This resulted in a sample of 691 subjects, with 279 cases and 412
controls. The University of Southern California Institutional Review Board reviewed
and approved the study. All subjects gave informed consent.

168
7.2.2 Data collection
The biologic mother of each case and control provided detailed information on
demographics, family history of asthma, feeding practices in infancy, day care
attendance, household environment (pets, cockroaches, and wood smoke, oil, or
exhaust), and farm related exposures (crops or dusts, farm animals, herbicide, and
pesticides) by a structured telephone interview. In the absence of biologic mother (i.e.,
4.7% of the cases and 9.7% of the controls), the biologic father, stepmother, or
guardian was interviewed.

7.2.3 Exposure assessment
For the environmental exposures, including exposures to cockroach, pets, farm
animals, herbicide, and pesticide, we recorded whether the child was ever exposed or
never exposed. To have a surrogate measure of particulate air pollutant exposures at
home, we asked about child's exposure to wood/oil smoke, soot, or exhaust. Similarly,
for exposure to farming lands, we asked about the exposure to farm crops or dust. If
the child had had such exposures, we sought information about the ages when those
exposures occurred. On the basis of the patterns of exposure in participating children,
we were able to define exposure in three periods: a) never exposed, b) exposed since
first year of life that continued after 1 year of age, and c) exposed only after first year
of life.

169
We defined exclusive breast-feeding as breast-feeding for at least 4 months after birth
without any supplement use. We recorded the total number of siblings (sibs; including
half-sibs), number of older siblings at birth, and birth order of the child under study.
We categorized the number of siblings at birth into five categories: none, one, two,
three, and more than three. We also collected information about any day care center
attendance before age 5 and the age when the child first attended such a center.

7.2.4 Outcome assessment
We defined asthma status using responses to the question "Has a doctor ever
diagnosed this child as having asthma?" We classified the age of onset into early (by 3
years of age) and late (after 3 years of age) onset. An asthma case was assigned as
having persistent asthma if the child had a) one or more episodes of asthma in the 12
months before study entry, b) any wheezing in the 12 months before study entry or
after starting first grade, or c) medication use for asthma in the 12 months before study
entry or after starting first grade. Of the 279 cases, 47 (16.8%) had early transient
wheezing, 166 (59.5%) had early persistent asthma, and 66 (23.7%) had late-onset
asthma.

7.2.5 Assessment of confounders and effect modifiers
Maternal smoking during pregnancy was assessed as ever/never as well as pack-years
of smoking. Secondhand tobacco smoke exposure was defined using the number of

170
household smokers (none, 1, > 1) during infancy. Family history of asthma or allergy
was defined as any first-degree relative with a diagnosis of asthma or allergy. Yearly
family income at the study entry was grouped into six categories: < $7,500, $7,500-
14,999, $15,000-29,999, $30,000-49,999, $50,000-99,999, and $100,000. Maternal
education at study entry was categorized into 5 groups: < 12th grade education,
completed 12th grade, some college, completed college, and some graduate education.
Race/ethnicity was grouped into four categories: non-Hispanic whites, Hispanics,
African Americans, and Asians and others.

7.2.6 Statistical analysis
Odds ratios (ORs) of physician-diagnosed asthma were estimated by fitting
conditional likelihood logistic regression models accounting for the countermatched
sampling using the methods described by Langholz and Goldstein.
12
The number of
nonparticipants, including those who declined to participate and those who could not
be contacted, was considered in the likelihood. Pairwise conditional logistic regression
models were used to assess the role of the exposures in different subgroups of asthma
(i.e., early transient wheezing, early persistent, and late-onset asthma) and on age at
asthma diagnosis (i.e., asthma diagnosis by age 3 vs. diagnosis after age 3).

We investigated whether education, income, race/ethnicity, secondhand smoke, and
maternal or family history of asthma confounded the associations between the

171
exposures of interest and asthma. Potential confounding covariates were included in
final models if their inclusion resulted in a 10% change in the parameter estimate. To
investigate whether any of these characteristics modified the associations of the
exposures of interest with asthma, we compared conditional logistic regression models
with and without appropriate interaction terms using likelihood ratio tests. All tests
were two-sided at a 5% significance level. We used the statistical software package
(SAS, version 8.2; SAS Institute Inc, Cary, NC) for all analyses.

7.3 Results
Most of the study subjects were white and male and had middle socioeconomic status
(SES) with an annual family income of US$30,000-100,000 (Table 7.1). Family
history of asthma was more common among cases than among controls (41.9 vs.
20.6%; p = 0.0002). However, there was no statistical difference in maternal education
level, yearly family income, or access to health care measured in terms of health
insurance coverage between cases and controls.

Exposure to wood or oil smoke, soot, or exhaust was significantly associated with
early-life asthma (Table 7.2). Children ever exposed to wood or oil smoke, soot, or
exhaust was at 1.6-fold higher risk of asthma than those who were never exposed [OR
= 1.61; 95% confidence interval (95% CI), 1.03-2.51]. This association appeared
stronger when exposure occurred in the first year of life (OR = 1.74; 95% CI, 1.02-

172
Table 7.1. Selected characteristics of the counter-matched case-control study participants selected
from the Children’s Health Study.
Case
a

N (%)
Control
a

N (%)
Control frequency
corrected for sampling

b
N (%)
Gender
Male 177 (63.4) 234 (56.8) 1382 (52.3)
Female 102 (36.6) 178 (43.2) 1259 (47.7)

Race/Ethnicity
Non-Hispanic White 164 (58.8) 266 (64.6) 1524 (57.7)
Hispanic White 66 (23.7) 89 (21.6) 792 (30.0)
African-American 13 (4.6) 22 (5.3) 96 (3.6)
Asians and others 36 (12.9) 35 (8.5) 229 (8.7)

Maternal Education
< 12
th
grade 19 (6.9) 54 (13.4) 313 (12.2)
12
th
grade 63 (22.8) 101 (25.0) 686 (26.6)
Some college 137 (49.6) 195 (48.3) 1127 (43.7)
College 24 (8.7) 22 (5.4) 212 (8.2)
Some graduate 33 (12.0) 32 (7.9) 239 (9.3)

Annual family income (U.S. dollars)
< $7,500 17 (6.8) 28 (7.7) 100 (4.2)
$7,500 – $14,999 20 (8.0) 58 (15.9) 320 (13.4)
$15,000 – $29,999 40 (16.0) 59 (16.2) 478 (20.1)
$30,000 – $49,999 58 (23.0) 98 (26.8) 654 (27.4)
$50,000 – $99,999 99 (39.4) 102 (27.9) 662 (27.8)
> $100,000 17 (6.8) 20 (5.5) 170 (7.1)

Health insurance coverage
No 26 (9.4) 62 (15.2) 447 (17.0)
Yes 250 (90.6) 346 (84.8) 2180 (83.0)

Family history of asthma
No 150 (58.1) 296 (79.4) 2008 (80.4)
Yes 108 (41.9) 77 (20.6) 489 (19.6)

In utero exposure to maternal smoking
No 211 (75.6) 149 (36.2) 2154 (81.6)
Yes 68 (24.4) 263 (63.8) 487 (18.4)
a
Numbers do not necessarily add up to the total number of cases and controls because of missing data.

b
Predicted number of controls in the cohort based on the sampling plan.

2.96). In subgroup analysis, exposure to wood/oil smoke, soot, or exhaust was
positively associated with both early- and late-onset asthma. However, the ORs were
statistically significant for early transient wheezing, for which exposure since the first

173
year of life was associated with more than 5-fold increased risk (OR = 5.65; 95% CI,
1.97-16.20).

Children ever exposed to cockroaches were also at significantly higher risk for
childhood asthma (Table 7.2). Children exposed to cockroaches in their infancy were
at 2-fold higher risk of asthma than those not exposed (OR = 2.03; 95% CI, 1.03-
4.02). Any cockroach exposure was associated with early transient wheezing (OR =
3.05; 95% CI, 1.01-9.23). This association derived from exposure to cockroaches after
the first year, which was associated with increased risk for early transient wheezing.
Exposure to pets was not associated with asthma in our data. Furthermore, specific
types of pets (e.g., dogs, cats, birds, and other furry animals) were not associated with
asthma (results not shown).

Compared with never-exposed children, children exposed to herbicide and pesticide in
the first year of life were significantly at higher risk of asthma, with ORs of 4.58 and
2.39, respectively (Table 7.3). Exposure beginning after the first year was not
associated with increased risk of asthma. When pesticide and herbicide exposures
were considered together, children exposed to any pesticide or herbicide in first year
of life were at 2.53-fold higher risk of asthma compared with children who were never
exposed to either of those (OR = 2.53; 95% CI, 1.25-5.09). The ORs for the
association of exposure to herbicide and pesticide and early persistent asthma were
largest for exposure beginning in first year of life (OR = 3.78; 95% CI, 1.70-8.41).

174
Table 7.2. Associations between early transient wheezing and any, early persistent and late onset asthma and exposures to wood/oil
smoke, soot or exhaust, cockroach and pets.
Controls Any asthma Early transient wheezing Early persistent asthma Late onset asthma
N N OR
a
(95% CI) N OR
a
(95% CI) N OR
a
(95% CI) N OR
a
(95% CI)
Wood/oil smoke, soot or exhaust exposure
Never 310 201 1 32 1 122 1 47 1
Ever 102 78 1.61 (1.03-2.51) 15 4.32 (1.80-10.38) 44 1.59 (0.94-2.70) 19 1.12 (0.52-2.43)
In 1
st
year and later 60 46 1.74 (1.02-2.96) 10 5.65 (1.97-16.20) 22 1.62 (0.84-3.10) 14 1.35 (0.58-3.16)
Not in 1
st
year 42 32 1.44 (0.77-2.68) 5 2.99 (0.86-10.41) 22 1.57 (0.77-3.21) 5 0.73 (0.22-2.42)

Cockroach exposure
Never 364 240 1 38 1 143 1 59 1
Ever 48 39 1.57 (0.89-2.75) 9 3.05 (1.01-9.23) 23 1.44 (0.73-2.84) 7 1.32 (0.46-3.88)
In 1
st
year and later 27 26 2.03 (1.03-4.02) 6 2.27 (0.60-8.60) 16 2.13 (0.95-4.78) 4 1.85 (0.51-6.69)
Not in 1
st
year 21 13 0.99 (0.41-2.42) 3 5.09 (1.02-25.43) 7 0.66 (0.21-2.10) 3 0.85 (0.19-3.92)

Exposure to pets
Never 82 58 1 9 1 34 1 15 1
Ever 330 221 1.42 (0.88-2.29) 38 2.61 (0.89-7.71) 132 1.41 (0.80-2.47) 51 0.73 (0.32-1.64)
In 1
st
year and later 224 146 1.48 (0.88-2.47) 23 2.34 (0.72-7.55) 90 1.47 (0.80-2.68) 33 0.78 (0.32-1.90)
Not in 1
st
year 106 75 1.35 (0.78-2.33) 15 2.90 (0.91-9.25) 42 1.32 (0.69-2.53) 18 0.67 (0.27-1.67)

a
Odds ratios are matched on age, gender and community of residence, counter matched on in utero maternal smoking and adjusted for race/ethnicity.

175
Table 7.3. Associations between early transient wheezing and any, early persistent and late onset asthma and exposures to
herbicides and pesticides.
Controls Any asthma Early transient wheezing Early persistent asthma Late onset asthma
N N OR
a
(95% CI) N OR
a
(95% CI) N OR
a
(95% CI) N OR
a
(95% CI)
Herbicide exposure
Never 387 257 1 46 1 151 1 60 1
Ever 25 22 1.20 (0.58-2.47) 1 0.26 (0.02-4.36) 15 1.36 (0.61-3.01) 6 1.21 (0.40-3.68)
In 1
st
year and later 5 11 4.58 (1.36-15.43) 0 - 10 10.08 (2.46-41.33) 1 2.26 (0.19-27.43)
Not in 1
st
year 20 11 0.58 (0.24-1.39) 1 0.40 (0.02-9.52) 5 0.36 (0.12-1.11) 5 1.09 (0.33-3.58)

Pesticide exposure
Never 367 239 1 43 1 141 1 55 1
Ever 45 40 1.61 (0.93-2.79) 4 1.27 (0.31-5.28) 25 1.82 (0.96-3.45) 11 1.54 (0.63-3.80)
In 1
st
year and later 23 23 2.39 (1.17-4.89) 3 2.56 (0.44-14.97) 17 3.58 (1.59-8.06) 3 0.92 (0.21-4.10)
Not in 1
st
year 22 17 1.00 (0.46-2.19) 1 0.34 (0.02-5.77) 8 0.74 (0.28-1.97) 8 2.05 (0.68-6.22)

Herbicide and/or Pesticide exposure
Never 360 232 1 43 1 138 1 51 1
Ever 52 47 1.53 (0.91-2.57) 4 1.26 (0.30-5.26) 28 1.62 (0.89-2.96) 15 1.83 (0.81-4.17)
In 1
st
year and later 22 25 2.53 (1.25-5.09) 3 2.56 (0.44-14.94) 18 3.78 (1.70-8.41) 4 1.33 (0.34-5.20)
Not in 1
st
year 30 22 0.93 (0.46-1.86) 1 0.31 (0.02-5.72) 10 0.64 (0.27-1.55) 11 2.14 (0.81-5.66)

a
Odds ratios are matched on age, gender and community of residence, counter matched on in utero maternal smoking and adjusted for race/ethnicity.

176
Adjustments for exposure to the farm environment did not substantially change the
estimates for herbicides and pesticides.

Exposure to farm animals, farm crops, or dust was associated with increased risk for
asthma (Table 7.4). Compared with never-exposed children, those who were ever
exposed to farm animals, farm crops, or dust had a 60% increased risk of asthma (OR
= 1.60; 95% CI, 1.01-2.52). The risk was larger in children who had these exposures
in their first year of life than in those who were exposed thereafter (OR = 1.88 vs.
1.32); however, this difference was not statistically significant. In subset analyses,
children with exposures to farm animals and farm crops/dust had elevated ORs for
both early transient wheezing and early persistent asthma; however, only the ORs for
the latter category reached statistical significance. Early persistent asthma was
statistically significantly associated with exposure in first year of life to farm animals
(OR = 3.03; 95% CI, 1.00-9.17) and farm crops/dust (OR = 2.06; 95% CI, 1.02-4.15).
Inclusion of herbicides and pesticides exposure status in the regression models did not
change the effect estimates for the farm environment.

Sibship size at the time of birth was inversely associated with asthma risk (p
trend
=
0.01; Table 7.5). Children who had four or more sibs were at 63% reduced risk of
asthma (OR = 0.37; 95% CI, 0.18-0.77) compared with children with one sib. Notably,
children with no siblings were at lower risk than were children with one sibling. These
associations were independent of day care attendance. We observed a weaker

177
Table 7.4. Associations between early transient wheezing and any, early persistent and late onset asthma and exposures to farm
animal and farm crops or dust.
Controls Any asthma Early transient wheezing Early persistent asthma Late onset asthma
N N OR
a
(95% CI) N OR
a
(95% CI) N OR
a
(95% CI) N OR
a
(95% CI)
Farm animal exposure
Never 361 234 1 41 1 139 1 54 1
Ever 51 45 1.62 (0.91-2.90) 6 1.32 (0.37-4.68) 27 1.67 (0.84-3.33) 12 1.22 (0.47-3.17)
In 1
st
year and later 17 17 2.11 (0.89-5.00) 2 3.45 (0.58-30.35) 12 3.03 (1.00-9.17) 3 0.72 (0.16-3.20)
Not in 1
st
year 34 28 1.41 (0.72-2.76) 4 0.88 (0.21-3.77) 15 1.29 (0.58-2.87) 9 1.60 (0.54-4.77)

Farm crop or dust exposure
Never 349 222 1 40 1 135 1 135 1
Ever 63 57 1.51 (0.91-2.52) 7 1.13 (0.36-3.52) 31 1.64 (0.89-3.03) 31 1.99 (0.91-4.33)
In 1
st
year and later 39 36 1.71 (0.94-3.14) 5 1.24 (0.31-4.91) 22 2.06 (1.02-4.15) 22 1.75 (0.65-4.71)
Not in 1
st
year 24 21 1.20 (0.55-2.61) 2 0.98 (0.17-5.54) 9 0.97 (0.35-2.70) 9 2.30 (0.81-4.47)

Farm animal, crop or dust exposure
Never 317 195 1 35 1 117 1 43 1
Ever 95 84 1.60 (1.01-2.52) 12 1.59 (0.58-4.34) 49 1.72 (1.00-2.94) 23 1.48 (0.71-3.09)
In 1
st
year and later 49 45 1.88 (1.07-3.28) 7 1.92 (0.60-6.16) 28 2.33 (1.19-4.54) 10 1.32 (0.52-3.37)
Not in 1
st
year 46 39 1.32 (0.73-2.39) 5 1.20 (0.29-4.89) 21 1.21 (0.59-2.46) 13 1.64 (0.66-4.05)

a
Odds ratios are matched on age, gender and community of residence, counter matched on in utero maternal smoking and adjusted for race/ethnicity.

178
Table 7. 5. Associations between early transient wheezing and any, early persistent and late onset asthma and exposures to
breastfeeding, number of sibs and daycare attendance.
Controls Any asthma Early transient wheezing Early persistent asthma Late onset asthma
N N OR
a
(95% CI) N OR
a
(95% CI) N OR
a
(95% CI) N OR
a
(95% CI)
Number of sibs
Continuous (0-8 sibs) 412 279 0.88 (0.77-1.02) 47 0.79 (0.57-1.09) 166 0.93 (0.79-1.11) 66 0.91 (0.68-1.22)

One 119 110 1 21 1 60 1 29 1
Two 132 87 0.74 (0.45-1.19) 15 0.63 (0.23-1.75) 54 0.86 (0.47-1.58) 18 0.99 (0.40-2.43)
Three 75 39 0.76 (0.42-1.37) 4 0.68 (0.17-2.83) 24 0.77 (0.37-1.61) 11 1.47 (0.53-4.09)
Four or more 52 21 0.37 (0.18-0.77) 5 0.40 (0.10-1.60) 14 0.49 (0.20-1.20) 2 0.17 (0.03-0.93)
P
trend
0.01 0.22 0.13 0.24
None 34 22 0.56 (0.26-1.20) 2 0.53 (0.09-3.32) 14 0.76 (0.31-1.85) 6 0.51 (0.13-2.08)

Daycare attendance
Never 192 103 1 12 1 64 1 27 1
Ever (0-5 years) 220 176 1.60 (1.07-2.39) 37 2.93 (1.20-7.15) 102 1.55 (0.96-2.48) 39 1.57 (0.77-3.19)
Before 4 months 46 42 2.42 (1.28-4.59) 12 5.36 (1.33-21.50) 23 2.00 (0.96-4.17) 7 1.66 (0.51-5.45)
Between 4-12 months 30 26 1.57 (0.76-3.21) 3 1.01 (0.19-5.40) 22 2.13 (0.95-4.76) 1 0.45 (0.05-4.16)
After 1
st
year 144 108 1.42 (0.92-2.21) 20 3.27 (1.26-8.48) 57 1.29 (0.76-2.19) 31 1.74 (0.81-3.72)
P
trend
0.19 0.05 0.34 0.19

Exclusive breastfeeding
< 4 months 280 163 1 32 1 100 1 31 1
≥ 4 months 121 111 1.34 (0.88-2.04) 14 1.34 (0.54-3.33) 62 1.27 (0.77-2.11) 35 1.98 (0.96-4.07)

a
Odds ratios are matched on age, gender and community of residence, counter matched on in utero maternal smoking and adjusted for race/ethnicity.

179
association of asthma with maternal parity than sibship size (data not shown). Effect
of sibship size did not vary substantially by asthma categories.

Day care attendance itself was positively associated with early childhood asthma
(Table 7.5). Compared with children who never attended day care centers, those who
went to such a center had a 1.6 times higher risk of developing childhood asthma (OR
= 1.60; 95% CI, 1.07-2.39). This increased risk was highest when day care attendance
occurred before 4 months of age (OR = 2.42; 95% CI, 1.28-4.59). Although risk was
increased in all three disease categories, the ORs were stronger for early transient
wheezing. Day care attendance before 4 months of age was associated with more than
5-fold increased risk of early transient wheezing (OR = 5.36; 95% CI, 1.33-21.50).
Attending day care centers after 1 year of age also increased the risk of early transient
wheezing (OR = 3.27; 95% CI, 1.26-8.48).

We found no associations with exclusive breast-feeding and any asthma outcome. We
found no significant differences in the associations of breast-feeding with asthma in
children by history of maternal or family history of allergy or asthma. Family or
maternal history of asthma, secondhand tobacco exposure, maternal smoking during
pregnancy, gestational age, yearly family income, health insurance coverage, and
maternal education level did not confound the association between any of the early-
life exposures and asthma outcomes. Therefore, these variables were not included in

180
the final models. Furthermore, none of the associations between the exposures and
early-life asthma varied by family or maternal history of asthma or allergy.

7.4 Discussion
In our population-based study of early-life environmental exposures and asthma, we
found that exposures to cockroach; wood/oil smoke, soot, or exhaust; pesticide;
herbicide; farm environment; and early day care attendance were associated with
increased risk for early-life asthma. The associations were strongest when children
were exposed beginning in their first year of life or, in the case of day care attendance,
in the first 4 months of life. Thus, the present study, in the context of emerging
evidence, suggests that the etiology of childhood asthma is complex and may include
early-life environmental exposures as well as factors related to early allergic
sensitization.

The effect of wood or oil smoke and cockroaches on childhood asthma was largely
restricted to children with early transient wheezing. Combustion of wood liberates
nitrogen dioxide, carbon monoxide, sulfur dioxide, and particulate matter, which have
been associated with increased occurrence of respiratory illnesses.
13
Oil smoke
exposure has been shown to increase asthma risk significantly.
14
Particulate matter
from wood combustion significantly reduced lung function in elementary school
children.
15
Similarly, exposure to cockroach allergen was associated with almost a
two-fold increased risk of wheeze in the first year of life.
16, 17
In recent reports,

181
cockroach allergen was found to alter bronchial airway epithelial cell permeability by
induction of vascular endothelial growth factor
18
and was significantly associated
with specific serum immunoglobulin E (IgE) levels.
19
Our results are consistent with
observations that early transient wheezing is associated with reduced lung function
and/or increased reactivity of the airways in infancy and that exposure to combustion
products and/or cockroach allergen may be important in these pathophysiologic
processes.

The associations between asthma and the environmental exposures examined in this
study were not due to confounding by SES. Although lower SES was significantly
associated with sensitization to cockroach exposure and asthma prevalence in previous
studies,
20, 21
most of our subjects belonged to middle socioeconomic class as
evidenced by the relatively higher maternal education level and annual family income
> $30,000, and most had health insurance coverage. In this SES-homogeneous
population, we did not observe any significant association between asthma and
cockroach exposure with SES or race. In addition, subjects were matched on
community of residence, further restricting the variability in SES.

We did not observe an association between pet exposures and childhood asthma,
findings that are consistent with several birth cohort studies.
22-24
Although some
studies have found positive associations,
25, 26
others have found pets to be protective.
27,
28
In a review of 32 articles, presence of pets in the first 2 years of life was associated

182
with a nonsignificant 11% increase in asthma risk
29
. It is difficult to explore the
association of pet exposure and childhood asthma even in prospective studies because
of concerns over temporality and other lifestyle factors that might be associated with
pet keeping. For example, families with asthma or allergic disease might avoid
keeping pets. Further prospective studies are needed to examine the associations
between childhood asthma and age at pet exposure, duration of pet exposure, and
measured levels of allergens and endotoxin.

Although studies have observed positive associations between asthma and pesticide
and herbicide use in adults,
30, 31
data on pesticides and childhood asthma are limited.
We found that exposure to either pesticides or herbicides, beginning in the first year of
life, was associated with an increased risk for early-onset persistent asthma. The
exposures occurred in both farm and nonfarm settings in our study. Our results are
consistent with a previous study that reported > 3-fold increased risk of asthma in
children between 7 and 10 years of age who had at least 0.3 µg/L of the
organochlorine compound dichlorodiphenyldichloroethene in their blood.
32
It has been
suggested that children's hand-to-mouth behavior, closeness to the playground, low
ratio of skin surface to body mass, reduced ability to detoxify toxic substances, and
increased sensitivity of cholinergic receptors to pesticides make them more vulnerable
to the toxic effects of pesticides, especially during their early lives.
33-35
Moreover,
immature respiratory systems and immune systems as well as developing nervous
systems may be more vulnerable to the deleterious effects of pesticide and herbicide.

183
Given the widespread use of pesticides and herbicides in the home and farm
environments and the magnitude of the observed risks, additional studies of the role
these exposures in asthma etiology across childhood are needed.

Several European cross-sectional studies have suggested a reduced risk of asthma with
early-life exposures to a farming environment.
7, 36
It has been suggested that exposure
to a farming environment (e.g., livestock, dust, crop) causes higher levels of bacterial
endotoxin exposure, and the latter eventually leads to the production of several
cytokines (e.g., interleukin-12, interferon- γ) that tip the balance toward the T
H
1- over
T
H
2-mediated immunity, thereby reducing asthma risk.
8
However, we did not see such
an inverse association with early-life farm exposures in our study. In fact, our results
suggest an increased risk for early-onset persistent asthma with farm-related exposure,
and we observed a significant increased risk of asthma in children who were exposed
to farm animals, crops, or dust in their first year of life. Other studies in the United
States and Canada have found that growing up in a farming environment is associated
with increased risk of asthma and that endotoxin exposures may increase asthma risk.
Explanations for this discrepancy between studies include differences in farming
practices, crops, and differences in dietary, lifestyle, and other unrecognized "rural"
factors that might influence this risk reduction in Europe but not in California and
other regions of the world. Moreover, it has been suggested that proximity of the
stables to the home and time spent in such stables might be important determinants for

184
assessing asthma risk in the European studies.
8
We were not able to address these
issues because we did not have appropriate information on our study subjects.

Our finding of a protective role of sibship size on asthma is consistent with the results
of many epidemiologic studies.
37, 38
Infections from older siblings during early life
have been proposed to prevent asthma by enhancing the T
H
1-mediated immunity.
39

However, the contrasting increased risk with early-life day care attendance is not
consistent with an explanation for the sibship association. Although parity was not as
strongly associated with asthma as sibship size, part of the protective effect of birth
order is likely to be imparted in utero, because studies have shown that cord blood
IgE, mononuclear cell proliferative responses, and essential fatty acids reduce
significantly with increasing parity or birth order.
40, 41
We also observed that children
with no siblings were at lower risk for asthma than were children with one or two
siblings, a finding that suggests the need for a more complex "hygiene hypothesis."

Our finding of an increased asthma risk for early transient wheezing with day care
attendance agrees with the findings of several cross-sectional studies.
38, 42
Moreover,
we observed that the risk of asthma is highest when children were sent to day care
centers before 4 months of age. This finding fits the hypothesis that respiratory
infections spread in early childhood from day care centers
43
and thereby increase the
risk of early transient wheezing.
44
If early-life infections protected children from
asthma, then we would have expected to observe a reduced risk of developing asthma

185
in children sent to day care centers in their early lives. Although we observed a
significant reduction in asthma risk in children with larger sibship size, day care
attendance was not protective for asthma occurrence in any of our asthma categories.
Taken together, our data support the hypothesis that early-life infections increase the
risk for early transient wheezing, and the protective effect of having many siblings
may result from differences in the in utero environment with successive pregnancies
or other aspects of lifestyle in larger families.

The present study has several strengths as well as some limitations. Our study was
nested in a large population-based cohort of children from 12 communities with a
wide range of exposures. We used a well-characterized cohort as our population and
employed an innovative sampling design to maximize efficiency while minimizing
confounding. However, our results are based on cross-sectional data and are subject to
the biases of this design. We defined asthma status using parental report of physician-
diagnosed asthma. Although medical practice may vary among providers, this case
definition has been widely used in epidemiologic studies of asthma. Parental report of
physician diagnosis has been found to accurately reflect physician diagnoses.
45
We did
not use parental recall of early-life wheezing episodes because recall of transient
wheezing is less complete.

Our environmental exposure assessment was broad and based on questionnaire
responses. It is likely that inaccurate recall produced some misclassification in

186
exposure status. However, because it is unlikely that a mother of a case or a control
would differentially recall her child's exposures during and after his or her first year of
life, this misclassification is likely nondifferential. Furthermore, most of the children's
exposures continued beyond age 5 (73.6% for cockroach and > 90% for all the other
exposures), suggesting that their home environment did not change appreciably in
relation to these exposures over time or after the children were diagnosed with asthma.
In this situation, we believe that recall was accurate enough to obtain the information
to classify subjects for these chronic exposures.

The temporal relationship between exposure and outcome is always a concern when
assessing the validity of a study that collected data cross-sectionally. Because many of
the exposures of interest in this study are not widely appreciated as asthma risk
factors, the retrospective recall in this study would likely have been nondifferential
and would bias the ORs toward the null. One exception may be the reports about the
presence of pets in the home. Our lack of association may be caused by mothers of
children with asthma not reporting pets, because pets are often the focus of clinical
interventions. We do not believe that there is likely to be any bias in reporting the
number of children at home or child's age at attending day care. The latter might be
related to maternal occupation, and it seems unreasonable to assume that mothers
would fail to remember when they had sent their children to day care centers on return
to work. Furthermore, it is not likely that recall bias accounts for the stronger
associations in the first year of life, because recall of early-life exposure status by

187
mothers is unlikely to be more accurate for their child's first year of life than for later
years of life. Given that we observed associations using questionnaire-based exposure
status, these associations may be stronger if true exposure status was known and
misclassification nondifferential. We lacked information on some exposures of interest
including presence of fungi, molds, and gas stoves in the house. Levels of dust mites
are generally low in the southwestern United States and as such are unlikely to explain
our results. We cannot rule out the possibility of chance as an explanation for
observing some significant results in subgroup analyses.

In conclusion, our results suggest that environmental exposures and lifestyle factors
are important for early-life asthma development and both indoor and outdoor
environmental exposures in the first year of life may play crucial roles in the etiology
of childhood asthma. Exposures to herbicides, pesticides, and the farm environment in
the first year of life may increase the risk for early-onset persistent asthma, a subtype
of asthma associated with long-term morbidity. Interventions to reduce the burden of
asthma may need to target early life as a critical window for asthma pathogenesis.
Given the enormous burden from childhood asthma, further research is needed to
assess the role of these and other environmental exposures during critical windows of
development.

188
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192
Chapter 8: Summary and Future Research Plans

8.1 Summary
Asthma prevalence in children increased from 1960 to late 1990s and has reached a
plateau in the United States since 2000. The disease disproportionately affects children
across the globe and remains a significant public health problem. In the United States,
one in 12 children below 18 years of age is estimated to have an asthma diagnosis.
Clinical history still remains the mainstay in diagnosis of asthma, especially in
children below 5 years where lung function testing is not feasible. Therefore, asthma
can be best regarded a clinical syndrome that has significant phenotypic heterogeneity,
the latter not fully elucidated to date.

In addition to the established risk factors of asthma, such as family history of asthma,
child’s atopy, male sex and exposure to maternal smoking in utero, we identified some
additional prenatal and early life risk factors for childhood onset asthma using the data
from the Children’s Health Study. The primary findings of these analyses were:

1) Children born to asthmatic mothers were at reduced asthma risk when their
mothers ate oily fish (rich source of omega-3 polyunsaturated fatty acids) during
pregnancy. However, children were at increased asthma risk when their mothers
consumed commercially prepared fish sticks (poor source of omega-3 fats and

193
potential source of trans fats) during pregnancy irrespective of the maternal
asthma status. These associations were similar across asthma phenotypes.

2) Children born by C-section were at increased risk for asthma, hay fever, and
allergy compared with those who had a vaginal birth. The magnitude of the
elevated risk was similar for atopic and non-atopic asthma and for early persistent
and late onset asthma phenotypes.

3) Exposures to cockroach; wood/oil smoke, soot, or exhaust; pesticide; herbicide;
farm environment; and early day care attendance were associated with increased
risk for early-life asthma. The associations were strongest when children were
exposed beginning in their first year of life or, in the case of day care attendance,
in the first 4 months of life. We identified that the strength of these associations
somewhat varied by asthma phenotypes. Exposure to wood/oil smoke and
cockroach and daycare attendance were significantly associated with early
transient asthma but not with other asthma phenotypes. Because the sample sizes
available for early transient asthma was lower than the other two asthma
phenotypes, it is unlikely that the results could be explained by sample sizes.
Exposure to herbicides and/or pesticides and farm animal, crop or dust showed
stronger associations for early persistent than for late onset asthma phenotype.

194

Figure 8.1. Conceptual model of asthma pathogenesis in childhood. Throughout prenatal to early
childhood periods, complex interactions among environmental exposures, genetic and epigenetic factors
modulate lung and immune development. There is cross-talk between the airway and immunity in that
inhalant exposures modulate immune functions, while the latter then could modulate airway
pathophysiology. The aforementioned dynamic events occur throughout the in utero and early
childhood periods and are associated with asthma development. Because timing of exposure could have
differential impact on the growth and development of airways and immune functions, exposures in
utero and early childhood may have differential impact on asthma risk.

195
These findings highlight the importance of prenatal and early life exposures and
timing of such exposures on asthma occurrence. Based on the results of the analyses
and existing evidence, a conceptual model for asthma pathogenesis in childhood could
be envisioned (Figure 8.1). According to the model, complex interplay among
environmental, genetic and epigenetic factors could differentially impact lung
development and immune maturation from in utero to early childhood periods and
thereby affect the risk of asthma occurrence in childhood. These associations may vary
by asthma phenotypes.

8.2 Future Research Plans
A large body of evidence indicates that timing of exposures during prenatal and early
life is important in asthma pathogenesis in early childhood. During the critical period
of lung and immune development in early life, environmental exposures may have
greater impact on these biological systems. Furthermore, inherited susceptibilities
(e.g., genetics and epigenetics) could modulate the impact of environmental factors.

The data presented here examined the impact of environmental exposures at different
time points in early childhood; however, genetic influences on such exposures warrant
further investigation. To extend the present work and to further the understanding of
the mechanisms mediating the effects of prenatal and early life exposures on asthma
occurrence, several lines of investigation could be undertaken.

196
The role genetic variations in key genes in the oxidative/inflammatory pathway and
the joint influence of genetic and environmental factors for asthma occurrence in
children need to be evaluated. Because oxidative stress and immune dysregulation
(i.e., Hygiene Hypothesis) could explain increase asthma occurrence as observed in
the past several decades, initially studies could conducted to evaluate the relationship
between variations in genes in the oxidative/nitrosative stress pathways as well as
those in the T
H
1, T
H
2, and T-regulatory cell differentiation pathway and asthma
occurrence in children.

There is some consistency in findings across epidemiologic studies regarding a
protective role of maternal consumption of antioxidants (vitamin D, E and fish) during
pregnancy on asthma occurrence in children, with some evidence of larger protection
in children with maternal asthma (Manuscript 1; Chapter 5). Associations between
early childhood consumption of antioxidants and asthma occurrence are less
consistent. Whether dietary antioxidants consumed during pregnancy interact with
maternal-fetal functional genetic variants in the oxidative/nitrosative stress pathways
and could result in epigenetic changes remains to be investigated.

The evidence for an association between birth by cesarean section and increased
asthma risk is somewhat inconsistent and the underlying mechanisms for such
association have not been examined extensively. The indication for cesarean section
has changed over the last several decades and the ancillary care has improved. More

197
research is needed to examine the association between emergent and non-emergent
cesarean section and asthma in children. Data on delayed microflora development and
increased interleukin-13in children born by cesarean section came from isolated
studies. More work is needed in the context of indications of cesarean section and
compare these outcomes with children born by vaginal birth.

Although studies conducted in Europe showed protective effects of farm exposures on
asthma occurrence in children, the findings presented here (Chapter 7) found such
exposures to be associated with increased asthma risk. Location of the farm in relation
to home, time-spent in farm or with farm animals and objective measurement of
endotoxins and allergens (i.e., cockroach) could be useful to assess the level of
exposure during pregnancy and in early childhood. Longitudinally collected data from
pregnancy to infancy are needed to replicate the findings that timing of exposures has
differential impact on asthma occurrence. In addition, the influence of functional
variations in genes that mediates the effects of endotoxin (toll-like receptors, CD14),
chitin in insects (e.g., chitinases), and pesticide/herbicide (e.g., enzymes in the
metabolism of polyaromatic hydrocarbon, glutathione S-transferases) on the
association of such exposures and asthma development remains to be investigated.

Evaluation of intermediate phenotypes or biomarkers of inflammation will be useful to
determine whether those could predict asthma occurrence and could aid in further
characterizing asthma phenotypes. Evaluation of fractional exhaled nitric oxide (FE
NO
)

198
and inflammatory biomarkers in exhaled breath condensate (8-isoprostane, H
2
O
2
, pH)
are promising as they involve non-invasive techniques. These biomarkers also have
the potential to inform of the natural history of asthma when evaluated with lung
function and other respiratory health end points. In this setting, the role of genetic
variations in key pathways and interplay of genetic and environmental exposures
could provide better insights into the mechanisms that could relate these intermediary
phenotypes with asthma occurrence.

In addition to non-invasive tests, high-resolution computerized tomography (HRCT)
or magnetic resonance imaging (MRI) could also provide additional details about the
anatomic and functional characteristics of the airways beyond lung function
measurements in adults with and without asthma. Such imaging resources along with
genetic, environmental and lung function data have the potential to further our
understanding about the interrelationships between anatomic alterations and
physiologic parameters (such as lung function, FE
NO
) and how genetic and
environmental factors influence these relationships.

To conclude, evaluation of independent and combined influences of genetic and
environmental factors in key asthma etiologic pathways on intermediate anatomic and
physiologic respiratory health endpoints has the potential in understanding the
pathophysiologic mechanisms through which such factors are associated with asthma
occurrence in children. Given the enormous burden from childhood asthma, this

199
comprehensive, pathway-based approach is needed to assess the role of genetic and
environmental exposures during critical windows of development on asthma
occurrence and to identify preventive strategies to mitigate such burden.

200
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Abstract (if available)

Abstract Asthma is the most common chronic inflammatory disease in childhood. The disease often starts early in life with significant burden to children and their families and the healthcare system. An accumulating body of evidence indicates that both prenatal and early life exposures play uniquely important roles in asthma occurrence by modulating airway and immune functions. In addition, timing of such exposures during these periods is likely to modulate the growth and development of airways and immune functions. Extensive literature reviews were done to critically evaluate earlier work and to understand the mechanisms of the underlying associations. The findings of the analyses are encouraging. Using data from the southern California Children's Health study, both prenatal and early life exposures were found to be associated with asthma occurrence in children. Additionally, timing of exposure in infancy and family history of asthma modified some of these associations. Some of the associations were stronger for particular asthma phenotypes. Given the enormous burden from childhood asthma, further research is needed to assess the role of these and other genetic, epigenetic and environmental factors during critical windows of development across distinct asthma phenotypes. These findings also indicate that any intervention strategy to reduce the burden of asthma in young children should target prenatal and early life as a critical time point to modulate exposures to prevent disease occurrence.

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Asset Metadata

Creator Salam, Md. Towhid (author)

Core Title Early life risk factors for childhood asthma

School Keck School of Medicine

Degree Doctor of Philosophy

Degree Program Epidemiology

Publication Date 07/28/2009

Defense Date 06/18/2009

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag asthma,Cesarean section,environmental exposures,life course epidemiology,OAI-PMH Harvest,Pregnancy,prenatal exposures

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Gilliland, Frank D. (committee chair), Dubeau, Louis (committee member), Ingles, Sue A. (committee member), Langholz, Bryan (committee member), McConnell, Robert (committee member)

Creator Email msalam@usc.edu,towhids@yahoo.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-m2393

Unique identifier UC1310240

Identifier etd-Salam-3090 (filename),usctheses-m40 (legacy collection record id),usctheses-c127-567961 (legacy record id),usctheses-m2393 (legacy record id)

Legacy Identifier etd-Salam-3090.pdf

Dmrecord 567961

Document Type Dissertation

Rights Salam, Md. Towhid

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Repository Name Libraries, University of Southern California

Repository Location Los Angeles, California

Repository Email cisadmin@lib.usc.edu