GENDER — There are clear-cut gender differences in the prevalence of asthma. Childhood asthma tends to be a predominantly male disease, with the relative male predominance being maximal at puberty [1]. After age 20, the prevalence remains approximately equal until age 40, when the disease becomes more common in females. Reasons for gender differences are unclear and largely unexplored. Possible explanations include:
The greater prevalence of atopy (ie, evidence of IgE sensitization to allergens) in young boys.
Reduced relative airway size in boys compared to girls [2]. Smaller airway size may also contribute to the increased risk of wheezing after viral respiratory infections in young boys compared to girls. (See "Virus-induced wheezing and asthma: An overview".)
Differences in symptom reporting between boys and girls [3].
EARLY ABNORMALITIES IN PULMONARY FUNCTION — There may be changes in lung function that are present in childhood or even in neonatal life in individuals who subsequently develop symptoms of asthma.
Neonatal lung function — There is some evidence for the presence of physiologic differences shortly after birth in individuals who later develop asthma. Lung function in neonates can be measured non-invasively using tidal breathing flow-volume loops and passive respiratory mechanics. Using these methods, a prospective birth cohort of 802 healthy infants underwent pulmonary function testing at an average of three days of age [4]. Ten years later, 77 percent were contacted and reevaluated for the presence of asthma by history, standard lung function testing, exercise-induced bronchoconstriction (treadmill testing), methacholine challenge, and skin prick testing for allergic sensitization to aeroallergens. There were statistically significant associations between values for pulmonary function testing below the median for the cohort and the presence of asthma at 10 years with odds ratios between 1.58 and 2.18, depending on the measurement examined.
Airway hyperreactivity — Abnormal and exaggerated airway responsiveness to noxious stimuli is a central feature in the pathophysiology of asthma, and all patients with asthma have airway hyperresponsiveness (AHR) by definition. (See "Diagnosis of asthma in adolescents and adults".)
However, not all patients with AHR have symptoms of asthma [5]. Population-based studies of both adults and children have shown that the prevalence of asthma is two to three times lower than the prevalence of AHR [1]. Moreover, 20 to 50 percent of subjects with airway hyperresponsiveness are asymptomatic at the time of testing. (See "Bronchoprovocation testing".)
These observations indicate that asthma and airway hyperresponsiveness are not identical phenomena. Airway hyperresponsiveness appears to be a necessary, but not sufficient condition for the development of clinical disease. Furthermore, patients with AHR are at increased risk for the development of asthma [6].
One study in adolescents demonstrated that AHR frequently antedates and is associated with an elevated risk for wheeze onset and recurrent asthma, even after controlling for a variety of known risk factors [7]. This study investigated 281 children, aged five to nine years at the time of entry into the study, and followed voluntarily with airway challenges for up to six years. In a logistic regression model, the odds ratio (OR) for incident wheeze among those with airways responsiveness at a previous visit was 3.91 (95% CI 1.21-12.66), after adjustment for gender, current age in years, parental atopic and asthmatic status, personal smoking, exposure to passive smoke, any lower respiratory infection before two years of age, and personal atopy.
Another study prospectively evaluated 81 Chinese students aged 11 to 17 years who were found to have AHR in a population survey [8]. Eighty-eight age-matched students without AHR served as controls. Fifty students with AHR were asymptomatic, of whom 10 (20 percent) developed asthma over a two year period compared to only two of 88 (2 percent) in the control group. The severity of AHR appeared to predict which subjects would become asthmatic.
FAMILIAL HISTORY OF ASTHMA — There are clearly components of the asthma phenotype that appear strongly heritable, although these inherited components do not follow the simple Mendelian pattern and the specific genes responsible for these inherited components have yet to be identified. This topic is reviewed in greater detail elsewhere. (See "Genetics of asthma".)
ATOPY AND ALLERGENS — Atopy may be defined as the state of having IgE antibodies to specific allergens, which is a prerequisite for developing allergic disease. The association between asthma and other atopic conditions is well-documented. The "atopic march" is a term used to describe the pattern of onset of different allergic diseases that is observed in some atopic individuals. This pattern begins with atopic dermatitis in infancy and childhood, followed by the onset of allergic rhinitis and then asthma during later childhood and adolescence. Not all atopic patients develop all three conditions (eg, only about one-third of children with atopic dermatitis subsequently develop asthma) and there are other patterns of presentation of allergic diseases; however, these conditions are clearly associated.
Atopy — Serum levels of IgE, the class of antibody responsible for the most common form of respiratory allergy, appear to be closely linked with airway hyperresponsiveness, whether or not asthma symptoms are present. Elevations in total IgE levels indicate the presence of allergic sensitization, although this measurement provides no information about the specific allergens to which an individual is sensitized.
The International Study of Asthma and Allergy in Childhood (ISAAC) found a wide variation among 22 countries in the fraction of current wheeze attributable to atopic sensitization [9]. The association between wheeze and atopy increased in countries with higher economic development.
The Third National Health and Nutrition Examination Survey (NHANES) found that half of the asthma cases were attributable to atopy [10]. Skin testing of 12,106 subjects with a panel of 10 allergens was performed; atopy was defined as having at least one positive skin test.
In a study of 2657 subjects, the prevalence of asthma was closely related to the total serum IgE level, as well as the skin test reactivity [11]. Further analysis showed that asthma correlated better with IgE levels, while allergic rhinitis correlated more closely with skin test reactivity.
Another report evaluated 562 11-year-old children who had serum IgE levels determined from a birth cohort of 1037 New Zealand children [12]. The prevalence of diagnosed asthma was significantly related to the serum IgE level. Even among children without a diagnosis of asthma, the prevalence and degree of AHR increased with increasing IgE levels as follows:
AHR was present in 1 percent at an IgE level below 32 IU/mL
AHR was present in 12 percent with IgE levels of 100 to 315 IU/mL
AHR was present in 30 percent with IgE levels above 315 IU/mL
Allergen exposure — A consensus is emerging that indoor allergens play a significant role in the development of asthma, although it has been difficult to demonstrate a causative relationship, and the majority of these studies were performed on high risk groups [13-16]. At least one prospective study of allergen exposure in early childhood, carried out with a cohort from the general population, found that although a minimum threshold level of allergen was necessary for sensitization or asthma to develop, there was no dose-response relationship above that level [17].
The reunification of East and West Germany afforded a unique opportunity to study the effects of environmental exposure on the development of lung disease in two genetically similar populations [18]. The prevalence of asthma, atopy (assessed by skin testing), and AHR was greater in West German children than in their counterparts in East Germany. West German children had significantly greater rates of sensitization to mite, cat, and pollen allergens. In contrast, bronchitis was more prevalent in East Germany, where outdoor air pollution was greater. These investigators proposed that the difference in prevalence of asthma between East and West Germany was attributable to the increased prevalence of allergic sensitization to common aeroallergens among children in the western part of the country.
Sources of indoor allergens include house dust mites, animal proteins (particularly cat and dog allergens), cockroaches, and fungi. Changes that have made houses more "energy-efficient" over the years are thought to increase exposure to these allergens, thereby playing a role in the increasing prevalence of asthma [13,19].
House dust mite – In many areas, sensitization to the house dust mite (HDM) appears to have an important association with asthma, potentially contributing to between 65 percent and 90 percent of cases among children and young adults [6,13,20].
Alternaria mold – In the middle and western United States, where levels of dust mite allergen are low, sensitization and exposure to the ubiquitous mold Alternaria appears to be important for the later development of asthma.
Cockroach allergen – In studies of inner city asthma, sensitization to cockroach allergen has been shown to be a significant risk factor in the development of asthma [21,22]. In addition, morbidity from asthma in inner-city children is associated with the presence of cockroach allergy and exposure to high levels of cockroach allergen in bedroom dust [23].
Animal allergens – Early life exposure to indoor cat and dog allergens has been found to be both associated with and protective against the development of asthma [24,25]. It is possible that other exposures such as environmental tobacco smoke and pollution modulate the impact of early life animal allergen exposure, providing a partial explanation for the variation in development of asthma [25].
Farm animals – Exposure to farm animals early in life is negatively associated with the development of allergic disease. Whether this is due to increased exposure to allergens or increased exposure to a wide range of microbial exposures has been the subject of a number of studies. (See "Increasing prevalence of asthma and allergic rhinitis", section on 'Since 1960'.)
Environmental control studies — Studies examining the impact of environmental control measures for various allergens are hindered by several recurrent problems. Protocols in which a single allergen is targeted for reduction often fail to produce clinical benefit [26-28]. This is not entirely unexpected, because most allergic individuals are sensitized to multiple allergens, and it is possible that all relevant allergens must be controlled simultaneously. A large Canadian trial that did this found benefit for some atopic conditions, although not for airway hyperresponsiveness [29]. It may also be necessary to tailor the interventions to the specific sensitivities of the patients, which is technically demanding. In addition, reductions in the allergens in question may be significant compared to control groups, but it is not known to what degree most allergens must be reduced in order to prevent sensitization. Environmental control to reduced exposure to allergens is reviewed in more detail separately. (See "Allergen avoidance in the treatment of asthma and allergic rhinitis".)
RHINITIS — Adults with rhinitis are at greater risk than those without rhinitis for developing adult-onset asthma [30-32]. This was best demonstrated in a prospective multicenter study of 6461 adults, aged 20 to 44 years [33]. Subjects were randomly chosen from the general population, and a cohort without asthma was evaluated with questionnaires, allergen skin testing, serum specific and total IgE, pulmonary function testing, and bronchial responsiveness testing. Subjects were divided into four groups and followed for a mean period of 8.8 years. The probability of developing asthma during the observation period was:
For those without evidence of atopy or rhinitis – 1.1 percent
Atopy but no rhinitis – 1.9 percent
No atopy but with rhinitis (ie, nonallergic rhinitis) – 3.1 percent
With allergic rhinitis – 4 percent
The adjusted risk ratio for those with allergic rhinitis was 3.5 (95 percent confidence interval (CI) 2.1 to 5.9) and for non-allergic rhinitis, 2.1 (CI 1.6 to 4.5), after controlling for country of origin, sex, FEV1, total IgE, family history of asthma, baseline age, body-mass index, respiratory infections in childhood, and smoking.
ENDOTOXIN EXPOSURE — Endotoxins are inflammatory lipopolysaccharide molecules from gram-negative bacteria that are ubiquitous in the environment. Determinants of endotoxin in homes include both indoor sources (eg, pets, pests, humidifiers, kitchen compost bins) and outdoor air. In a nationwide study of 831 representative homes, there was an association between increasing endotoxin levels and diagnosed asthma, asthma symptoms in the past year, current use of asthma medications, and wheezing [34].
OCCUPATIONAL EXPOSURES — The European Community Respiratory Health Surveys (ECRHS and ECRHS-II) identified several occupations that are associated with an increased risk of new onset asthma; nursing and cleaning were responsible for the most cases [35]. Inhalational accidents (eg, fires, mixing cleaning agents, industrial spills) were also associated with an increased risk of new onset asthma.
In the Agricultural Health Study of 25,814 adult farm women, growing up on a farm was protective against asthma, but use of certain pesticides (eg, organophosphates) was associated with an increased risk of adult-onset atopic asthma [36].
POLLUTION
Outdoor — There is a known correlation between levels of air pollution and lung disease, but the association between air pollution and asthma is less clear. As an example, in a study of six cities in the United States, there was a direct relationship between the levels of particulate pollution and reported rates of chronic cough and bronchitis [37]. There was no association between particulate concentration and asthma, persistent wheeze, or hay fever.
It is possible that asthma is related to specific pollutants, while other respiratory diseases are related to total air pollution.
Studies in reunified Germany have provided data on two populations exposed to different levels of pollutants [18,38]. East Germany had consistently high levels of SO2 and other particulates, whereas West Germany had low levels of sulfur dioxide (SO2) but slightly higher levels of nitrogen dioxide (NO2). The prevalence rates of asthma and atopy were higher in the West German towns, while the rates of bronchitis were higher in the East German towns, suggesting at most a minor effect of air pollution on the prevalence of asthma [18,38].
A large epidemiologic study examined the correlation between asthma symptoms in 990 children in eight North American cities, and the ambient concentrations of five air pollutants [39]. There was a small positive correlation between symptoms and carbon monoxide and NO2 levels, a marginal correlation with SO2 levels, and no relationship with ozone levels or particulate matter.
An eight year prospective study found an association between the risk of asthma onset and incident asthma and both greater exposure to NO2 and living in close proximity to a major road [40].
Others studies have examined a possible role of diesel exhaust particles specifically, which are taken up by airway epithelial cells and may stimulate allergic-type immune reactions [41-44].
Indoor — Gas stoves are the primary source of indoor NO2. It is estimated that more than half of the households in the United States use gas stoves; thus, a large number of adults and children may be chronically exposed to NO2 [45].
In a study of 728 children (age <12 years) with asthma, patients in multifamily housing with gas stoves had an increased likelihood of wheeze (OR = 2.27, 95% CI 1.15-4.47), shortness of breath (OR = 2.33, 95% CI 1.12-5.06), and chest tightness (OR = 4.34, 95% CI 1.76-10.69) [45]. The association between gas stoves and respiratory symptoms did not exist in single family housing, suggesting that the relationship is most relevant to patients in lower socioeconomic groups.
RESPIRATORY INFECTIONS — Viral and bacterial respiratory infections are well-known triggers that can cause exacerbations in children and adults with asthma [46,47]. Whether respiratory infections can be a cause of asthma, however, is not known [48,49]. There are no conclusive epidemiologic data linking infections to causation of asthma in previously normal adults. Furthermore, certain respiratory infections may be protective in infants, not causative. In this section, respiratory infection refers to viral or unspecified infections; few studies have looked at the effect of bacterial infections.
Epidemiologic studies performed on samples of unselected children have suggested that frequent respiratory infection during infancy may protect against the later development of asthma [50]. An example of this effect comes from remote islands whose population has both a very low incidence of respiratory infections and strikingly high prevalence rates of asthma and atopy [51]. Similarly, the development of asthma, hay fever, or eczema has been shown to be inversely related to the number of older siblings or participation in day care [18,52-55]. Taken together, these observations suggest that in most children, respiratory infections early in life somehow delay or prevent the expression of allergic diseases later in life [52,56].
SMOKING AND EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE — Population-based studies appear to show a relationship between smoking and airway hyperresponsiveness. However, the presence of asthma in adults has generally been unrelated to smoking history, possibly reflecting a tendency for asthmatics not to become regular smokers or to smoke less than their non-asthmatic counterparts [1].
Active smoking — Several studies have demonstrated that active smoking increases the risk for developing asthma [57-59]. A 1996 longitudinal study of 5801 people born in 1958 who were part of a national British cohort has implicated smoking in the development of wheeze and asthma in young adults [57]. Subjects were followed up at the ages of 7, 11, 16, 23, and 33 years. Active smoking was strongly associated with the incidence of asthma and wheezing illnesses between the ages of 17 and 33 (OR=4.42, 95% CI 3.31-5.92) after controlling for a variety of factors, including gender, maternal age, birth order, gestational age, hay fever, eczema, father's social class, and maternal smoking. In addition, among the 880 children who developed asthma or wheezy bronchitis by age seven, relapse at age 33 after prolonged remission of childhood wheezing was more common among current smokers. A study of adolescents found that those who smoked ≥300 cigarettes per year had a relative risk of 3.9 for developing asthma, compared to their non-smoking peers [58].
Secondhand smoke — There is a growing body of evidence that secondhand smoke exposure is associated with the development of asthma in early life [25]. Maternal smoking is the most important cause of secondhand smoke exposure, because of the greater exposure of the child to the mother than the father [19]. (See "Secondhand smoke exposure: Effects in children".)
As an example, a cross-sectional analysis of the relationship of maternal cigarette smoking to the incidence of asthma in the first year of life found that the children of smoking mothers were 2.1 times more likely to develop asthma than were children of non-smoking mothers [60]. Similar findings were noted in another study in which the effect of maternal smoking was found in mothers of low educational level [61].
In adults, data on the effects of environmental tobacco exposure on nonmalignant lung disease are sparse. The association between passive exposure to tobacco smoke and respiratory symptoms was studied in a sample of 4197 non-smoking adults as part of the Swiss Study on Air Pollution and Lung Diseases in Adults (SAPALDIA Study) [62]. Passive exposure to tobacco smoke was associated with increases in the risks of doctor-diagnosed asthma (odds ratio = 1.39), wheezing, bronchitis, and dyspnea.
Prenatal exposure to maternal smoking — Prenatal exposure to smoking may also be important, being associated with reduced pulmonary function in the infant. One study, for example, evaluated the effect of prenatal maternal cigarette smoking on the pulmonary function of 80 healthy infants shortly after birth [63]. Maternal smoking was assessed by questionnaire reports and urine cotinine concentration at each prenatal visit. Pulmonary function (assessed as flow at FRC) was lower in infants whose mothers smoked compared to those whose mothers did not smoke.
Another report evaluated the effect of early levels of lung function on the subsequent occurrence of a wheezing lower respiratory tract illness in the first year of life [64]. Infants who developed a wheezing lower respiratory tract illness in the first year of life had lower pre-illness lung function compared to infants who did not wheeze and were more likely to have mothers who smoked during pregnancy. Reduced pulmonary function early in life increases the risk for wheezing and subsequently for asthma later in life.
It has been proposed that prenatal smoking exposes the fetus to the growth-retarding effects of tobacco and enhances airway-parenchymal dysanapsis (disproportionately small airways compared to the size of the pulmonary parenchyma). These changes may contribute to the postnatal expression of increased airway responsiveness and asthma [65].
Two other studies have examined the effects of prenatal and postnatal exposure to smoking on asthma and wheezing in children. The first study used a broad case definition to identify 620 schoolchildren aged seven to nine years in Cape Town with current asthma or wheeze in the last 12 months [66].
In bivariate analyses, maternal smoking, whether defined as ever smoking (OR=1.80), smoking during pregnancy (OR=1.97), smoking during the first year of the child's life (OR=1.70), or current smoking (OR=1.70) was significantly associated with current asthma/wheeze among the children. The number of cigarettes smoked daily by the mother and the number of household smokers were also related to current asthma/wheeze.
Further strengthening these findings, the children's cotinine-creatinine ratio was significantly associated with current asthma/wheeze (OR=1.61 for the highest quartile versus the lowest quartile).
In a multivariate logistic regression model controlling for a variety of known risk factors, maternal smoking during pregnancy (OR=1.87, 95% CI 1.25-2.81) and the number of household smokers (OR=1.15, 1.01, 1.30) remained significantly associated with current asthma/wheeze.
The second study examined the relationship between current and past exposure to maternal, paternal, and nonparental environmental tobacco smoke in the home and several measures of asthma and wheeze in a large sample of school-aged children (11,534 children) from 24 communities in the US and Canada [67]. Asthma was identified based on either an active diagnosis of asthma or use of medication for asthma. Wheeze outcomes were: any wheezing, wheezing with a cold, wheezing without a cold, persistent wheeze, shortness of breath with wheeze, awakening at night by wheezing, wheezing with exercise, medication for wheeze, emergency department visit for wheeze, and hospitalization for wheeze.
Children who were currently exposed had a significantly increased risk of reported wheeze with a cold (OR=1.65), emergency department visit for wheeze (OR=1.63), persistent wheeze (OR=1.42), shortness of breath with wheeze (OR=1.35), wheeze with exercise (OR=1.24), and medication for wheeze (OR=1.23) in past year. For most of the wheeze outcomes, there was an increasing risk associated with increasing number of smokers in the home and number of cigarettes smoked in the home per day.
Active asthma was significantly associated with exposure to environmental tobacco smoke in pregnancy only (OR=2.70, 95% CI 1.13-6.45), and no significant association was found for currently exposed children.
OBESITY — Age-adjusted prevalence rates for asthma and obesity are increasing in the United States. Experimental models, prospective cohort studies, population-based case-control studies, and a meta-analysis suggest that patients with an elevated BMI are at increased risk for developing asthma [68-74]. This risk may be greater for nonallergic asthma than allergic asthma [75].
A prospective cohort study of nearly 86,000 adults followed for five years showed a linear relationship between BMI and the risk of developing asthma [69]. The relative risk of developing asthma was 2.7 for patients in the highest BMI group compared with nonobese counterparts.
In a meta-analysis of seven prospective studies (333,102 subjects) that evaluated the impact of BMI on the incidence of asthma in adults, asthma was more likely in patients who were overweight or obese than in patients who had a normal body weight (odds ratio 1.5, 95% CI 1.27-1.80) [72]. The incidence of asthma increased as the BMI increased.
Increased BMI may also be associated with increased asthma severity [76].
Smaller studies have documented improved spirometry, decreased peak flow variability, reduced rescue medicine use, fewer asthma flares, and decreased subjective dyspnea in obese asthmatics who lost weight [71].
However, it is possible that the magnitude of this risk is overstated [77-82]. Some studies have been based on patient reports of dyspnea or the use of inhaled beta agonists, rather than objective evidence of airflow obstruction. When data from 16,171 participants in the Third National Health and Nutrition Examination Survey (NHANES III) were analyzed, obesity was an independent risk factor for dyspnea, but not for airflow obstruction [81]. Thus, although obesity is statistically associated with asthma, biologic causality has not been proven.
EARLY MENARCHE — Earlier menarche appears to increase the risk of developing asthma in young adulthood [83,84]. As an example, asthma symptoms and bronchial hyperreactivity are more common among adult women with menarche before the age of 11 years compared with menarche at age 13 or later based on a large multinational study [83]. In addition, both forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) are lower among women with earlier rather than later menarche. Adjustment for adult body mass index (BMI), age, height, education, and smoking status did not alter these findings.
MEDICATION USE — Epidemiologic studies have found associations between the development of asthma and both the regular use of acetaminophen and exposure to antibiotics during infancy. However, these studies have inadequately accounted for confounding bias. Both of these associations warrant further study.
Acetaminophen — Acetaminophen/paracetamol use has been postulated to be a risk for asthma because this agent induces depletion of the antioxidant glutathione in lung tissue [85-91]. As a result, oxidative damage may occur, prostaglandin E2 production increases, and Th2 processes may be promoted. Conflicting results have been reported in population based studies of acetaminophen/paracetamol use and asthma.
Several studies have noted a dose-dependent relationship between the regular use of acetaminophen (or paracetamol) and the risk of developing allergic disease in general and asthma in particular [92-101]. In the largest of these, parents of 205,487 children were asked retrospectively about paracetamol use in the first year of life and about current asthma symptoms [100]. Use of paracetamol in the first year of life was associated with a small increase in risk of asthma at age six to seven; current paracetamol use was associated with a dose dependent increase in risk of asthma symptoms. The effect was also noted in both adults and in offspring of mothers taking regular acetaminophen during pregnancy [102].
In another population based study, regular acetaminophen use, but not aspirin or ibuprofen, was linked to the risk of reporting asthma or chronic obstructive pulmonary disease, even after controlling for smoking [93].
Many of the studies that have described an association between acetaminophen use and asthma are retrospective and therefore subject to recall bias [103,104]. An additional problem with studies evaluating over-the-counter medications such as acetaminophen is the possibility that the indication for the medication introduces confounding bias. As an example, asthmatics and those who are at risk for developing asthma are more likely to have co-morbidities (eg, respiratory infections) for which they may take acetaminophen for its analgesic or antipyretic effects. In a study of 1164 children enrolled in a birth cohort, intake of acetaminophen during the first year of life was associated with wheezing at two years of age; however, this association was significantly attenuated when respiratory infection was controlled for [105].
To reduce the risk of confounding bias, the Melbourne Atopy Cohort Study obtained frequent prospective documentation of paracetamol use and its indication in 620 children with a family history of allergic disease [106]. After adjustment for the frequency of respiratory infections, the association between paracetamol use and parental report of asthma at age six or seven disappeared. Paracetamol use for nonrespiratory indications was not associated with asthma.
Antibiotics during infancy — Exposure to antibiotics during infancy has been associated with the development of asthma in later childhood. The "microflora hypothesis," or the dependency of the neonatal gut on the presence of normal microflora for the development of tolerance in early life, has been postulated to explain this association. In keeping with this theory, sterilization of the gut with antibiotics causes increased allergic disease in mouse models [107].
In a meta-analysis of four retrospective and four prospective studies (12,082 infants), development of childhood asthma was more likely among infants exposed to antibiotics during the first year of life compared to unexposed infants (odds ratio 2.05, 95% CI 1.41-2.99) [108].
When the authors stratified their analysis by type of studies, they found that the effect of antibiotics in early life was stronger in the retrospective studies (odds ratio 2.82, 95% CI 2.07-3.85) than in the prospective studies (odds ratio 1.12, 95% CI 0.88-1.42). This strongly suggests that the findings in the retrospective studies were the result of uncontrolled confounding bias or recall bias. The meta-analysis of the prospective studies suggested that exposure to antibiotics in infancy was not a major risk for the development of asthma.
Postmenopausal hormone replacement therapy — Observational studies have reported a modest increase in the incidence of asthma among postmenopausal women taking hormone replacement therapy [109-113]. Some studies have reported an increased risk associated with combination estrogen-progesterone therapy and others only with unopposed estrogen. In one study, prior histories of allergy or never-smoking appeared to enhance the risk [113].
PRE- AND PERINATAL FACTORS — Attention has increasingly been focused on the prenatal and perinatal period to identify factors which may help predict the development of asthma and wheezing lower respiratory illnesses. Prenatal exposure to maternal smoking has been discussed above. Other perinatal factors that have been studied include reduced lung function in early infancy, maternal age and diet during pregnancy, prematurity, in utero exposure to antibiotics, head circumference at birth, and mode of delivery.
Increased IgE levels in infant cord blood, in conjunction with a family history of atopy, are associated with the development of atopic disease in childhood [114,115]. Increased cord blood IgE (which is believed to be of infant origin), in turn, was found to be correlated with maternal allergen sensitization, age, and maternal IgE levels, infant male sex, lower socioeconomic status, and Hispanic ethnicity [116]. The interrelationship of these factors require further study, although it suggests that both genetic and environmental factors influence the atopic diathesis, even before birth.
Maternal age — Infant mortality due to respiratory illnesses is inversely related to maternal age. Fewer studies have examined the relationship between infant respiratory morbidity and maternal age.
In one study, for example, the incidence of lower respiratory tract illnesses during the first year of life was evaluated in 1246 infants enrolled at birth between 1980 and 1984 in Tucson, Arizona [117]. The mothers were divided into five age groups: less than 21, 21 to 25, 26 to 30, 31 to 35, and greater than 35. The incidence of wheezing lower respiratory tract illnesses was inversely related to maternal age; in contrast, the incidence of nonwheezing respiratory illnesses was independent of maternal age. The odds ratio for a wheezing lower respiratory tract illness in infants was 2.4 for infants whose mothers were less than 21 years of age compared to mothers over 30 years of age.
This study did not address the risk of asthma, which is not necessarily predicted by wheezing illnesses in infancy. Young maternal age as a risk factor for the development of asthma was studied in a case-control study of 457 newly diagnosed asthmatics among 3 to 4 year old children in Quebec [118]. Compared to children of mothers who were older than 30 years, children born to mothers younger than 20 years had the highest risk of developing asthma, with an adjusted odds ratio of 3.48.
Maternal diet during pregnancy — Since most asthma has its origins in childhood, early nutrition, including prenatal exposure to nutrients, may be relevant as a risk factor for the development of asthma and allergies [119]. Conflicting results have been reported, possibly due to inherent difficulties with assessing diet and controlling for confounders [119-121].
Maternal intakes of the antioxidant vitamin E, zinc, and vitamin D may modulate the risk for wheezing and asthma in young children [122-126]:
In the SEATON cohort, a birth cohort of over 1,000 children in Scotland, maternal total intake (diet + supplements) of vitamin E in the highest tertile correlated to reduced development of wheezing symptoms in two year old children, compared with intakes in the lowest tertile (adjusted OR = 0. 49) [122]. These protective effects of vitamin E for wheezing at two years translated to a protective effect for asthma as the children turned five years old [123]. In addition, maternal zinc intake was also inversely associated with active asthma in the children (adjusted OR = 0.72).
Similarly, in an analysis of a birth cohort of over 1,000 in Massachusetts, performed by the authors, higher maternal intakes of vitamin E and zinc were inversely associated with recurrent wheezing in two year old children [124].
An inverse association between maternal intake of vitamin D during pregnancy and risk of recurrent wheeze in young children in northern climates has also been identified [125-127]. Vitamin D deficiency has become more prevalent as people spend more time indoors, particularly in northern areas, and with increasing use of sunscreen [128]. In two cohorts, one in the northeastern United States and the other in northern Scotland, low maternal dietary and total vitamin D intakes during pregnancy were associated with increased wheezing symptoms in children at ages three to five years. These associations were independent of maternal smoking status, maternal intake of vitamin E, zinc, and calcium, and also vitamin D intake by the children. In a third cohort, studied in Finland, higher maternal vitamin D intake from food during pregnancy was associated with lower risks for asthma and allergic rhinitis in five-year old children [127]. Vitamin D has been implicated in immunomodulation of multiple cell types, notably dendritic and T regulatory cells. (See "Vitamin D and extraskeletal health", section on 'Immune system'.)
In a prospective cohort study, high adherence to a Mediterranean diet during pregnancy was associated with a reduced risk of wheeze and atopy in the offspring at age 6.5 years [129]. However, another study (n=14,062 children) found no effect of dietary pattern on the development of asthma after controlling for confounders [130].
Breastfeeding — This topic is reviewed in detail separately. (See "The impact of breastfeeding on the development of allergic disease".)
Prematurity — Retrospective studies and meta-analyses have suggested that prematurity is another perinatal risk factor for asthma [131-133]. One report, for example, evaluated the significance of gestational age, birth weight, mechanical ventilation after birth, and a family history of asthma on the development of childhood asthma in a cross-sectional study of 5030 German children aged nine to 11 years [132]. The prevalence of asthma was significantly increased in premature girls (OR=2.6), particularly in those who required mechanical ventilation after birth (OR=3.7). No such difference could be demonstrated for boys. Prematurity was a significant risk factor for both recurrent wheezy bronchitis and asthma in a second cross-sectional study of 1,812 primary school children [133]. Prospective studies are needed to confirm these findings.
Mode of delivery — Delivery by Cesarean section may increase the risk of childhood asthma compared with vaginal delivery [134-139]. A population-based cohort study of 1.7 million singleton births found an increased risk of childhood asthma with both planned and emergency cesarean section (HR 1.52, CI 1.42 to 1.62) [138]. One possible explanation is that neonates born by vaginal delivery acquire most of their intestinal flora by swallowing their mother's vaginal fluid during birth; perinatal exposure to microbes on passage through the birth canal then influences early immune modulation. This is an extension of the "hygiene hypothesis" that microbial exposure and infections during early childhood (ie, postnatally) protect against the development of asthma and other allergic disease; however, data in support of this hypothesis are conflicting [134-137,140-149].
A small study found that children born by Cesarean section had increased levels of IL-13 and IFN-gamma compared with children born vaginally [148]. Increased levels of these cytokines have been associated with the subsequent development of asthma and allergies.
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