Official reprint from UpToDate®

www.uptodate.com © 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Risk factors for asthma

AUTHORS: Augusto A Litonjua, MD, Scott T Weiss, MD, MS
SECTION EDITORS: Peter J Barnes, DM, DSc, FRCP, FRS, Robert A Wood, MD
DEPUTY EDITOR: Paul Dieffenbach, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Aug 2023.

This topic last updated: Jun 26, 2023.

INTRODUCTION

Asthma is a respiratory condition that likely results from complex interactions between multiple
environmental and genetic influences. Numerous risk factors for asthma have been identified,
largely through association studies. Proposed risk factors for asthma vary with the age of
asthma onset and timing of exposures and behaviors relative to the onset of asthma. For most
of these risk factors, the degree to which the risk factors can be mitigated to change the
likelihood of asthma is not known.

Risk factors for the development of asthma are presented here. The epidemiology, genetics,
natural history, and triggers of asthma are reviewed separately. (See "Epidemiology of asthma"
and "Natural history of asthma" and "Trigger control to enhance asthma management" and
"Genetics of asthma".)

PRE- AND PERINATAL FACTORS

Attention has increasingly focused on the prenatal and perinatal period to identify factors that
may help predict the development of asthma and wheezing lower respiratory illnesses. (See
'Prenatal exposure to maternal smoking' below.)

Genetics and familial history — 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 and how
they interact with each other and with environmental exposures have yet to be determined.
Potential genetic contributions to asthma are reviewed in greater detail separately. (See
"Genetics of asthma".)

Maternal age — Limited data suggest that increasing maternal age at delivery (age >30 years)
is associated with a lower risk of asthma and higher adult lung function in the offspring,
compared with younger maternal age [1-4].

● In the European Community Respiratory Health Survey (10,692 adults), increasing

maternal age at delivery was associated with a higher forced expiratory volume in one
second (FEV1), although this was more consistent among female than male offspring [3].
Asthma decreased with increasing maternal age (odds ratio [OR] 0.85, 95% CI 0.79-0.92) in
females, but not males.

● Young maternal age as a risk factor for the development of asthma was studied in a case-
control study of 457 children 3 to 4 years of age with newly diagnosed asthma [2].
Compared with 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 [5]. Conflicting results have been reported, possibly due
to inherent difficulties with assessing diet and controlling for confounders [5-9].

Vitamin D — Vitamin D deficiency has been documented in many counties worldwide [10],
and coincides with other epidemiologic patterns of worsening asthma incidence, including a
rise in asthma and allergies in countries with a Westernized lifestyle, a latitude away from the
equator, and increased sun-avoidance behaviors including widespread sunscreen use [11].
Furthermore, some evidence suggests that high-dose maternal vitamin D supplementation (eg,
2000 to 4000 international units/day) during pregnancy reduces the risk of early life (up to age
three) asthma/wheeze in the offspring [11-14]. Recommendations regarding high-dose vitamin
D supplementation for women whose children are at high risk of asthma (eg, one or both
parents have asthma) are provided separately. (See "Management of asthma during
pregnancy", section on 'High-dose vitamin D'.)

● Observational data are conflicting regarding the relationship between maternal vitamin D
status and the risk of asthma. An inverse association between maternal intake of vitamin
D during pregnancy and risk of recurrent wheeze in young children in northern climates
has been noted in some studies [15-17]. In two cohorts, one in the northeastern United
 States and the other in northern Scotland (SEATON), low maternal dietary and total
vitamin D intakes during pregnancy were associated with increased wheezing symptoms
in children at ages three to five years [15,16]. 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 [17]. Follow-up through 10 years of age in the SEATON
cohort showed that the children born to mothers with high vitamin D intake in pregnancy
had lower odds of being diagnosed with asthma (OR per intake quintile 0.86, 95% CI 0.74-
0.99) [18].

Other studies, however, that measured either maternal vitamin D status or cord blood
vitamin D levels did not confirm these associations [19-21], but study design issues in both
types of studies (ie, studies using estimation of vitamin D intake and studies that
measured vitamin D levels at one point in time) precluded definitive conclusions [22].

● The Vitamin D Antenatal Asthma Reduction Trial (VDAART) examined the effect of vitamin
D supplementation in a trial that randomly assigned 881 women between the gestational
ages of 10 to 18 weeks to 4000 international units vitamin D3 plus a multivitamin that
contained 400 international units vitamin D3 per day or placebo plus a multivitamin that
contained 400 international units vitamin D3 per day [12]. The primary outcome was
asthma or recurrent wheeze by age three years, and 806 children provided information.
The results showed a 20 percent reduction in the risk for asthma or recurrent wheeze in
the children born to mothers in the intervention arm compared with the children born to
mothers in the placebo arm (hazard ratio [HR] 0.8, 95% CI 0.6-1.0), although this did not
reach statistical significance. A follow-up analysis at the time of the children's sixth
birthday found no effect of maternal vitamin D3 supplementation on asthma or recurrent
wheeze in an intention-to-treat analysis or with stratification according to maternal
hydroxyvitamin D level during pregnancy [23].

● The Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2010) recruited 623

women at 24 weeks of gestation to take either vitamin D3 2400 international units/day or
matching placebo; all women received 400 international units vitamin D3 as part of
prenatal care [24]. The primary outcome was onset of persistent wheeze in the first three
years of life, and a secondary outcome was asthma at age three years; 581 children were
included in the analysis. Vitamin D3 supplementation during pregnancy caused a non-
significant decrease in the risk for both persistent wheeze (HR 0.76, 95% CI 0.52-1.12) and
asthma at age three years (OR 0.83, 95% CI 0.50-1.36). Using a generalized estimating
 equations model, a follow-up analysis of the children through age six years yielded similar
non-significant results (OR of yearly prevalence of persistent wheeze or asthma 0.87, 95%
CI 0.59-1.28) [25].

● While the results of the above trials did not meet statistical significance, the effect of
prenatal vitamin D3 supplementation was of similar magnitude and direction in both trials
(HR of 0.8 for VDAART and 0.76 for COPSAC2010), suggesting a true effect. One possible
explanation is that baseline vitamin D status may affect the response to vitamin D
supplementation [26], and since baseline vitamin D level was not a criterion for entry in
either trial, this may have biased the results toward the null.

This notion was tested in a secondary analysis of the VDAART data [12]. When subjects
were stratified by the level of 25-hydroxyvitamin D at entry into the trial [27], there was no
effect of initial vitamin D level on wheeze or asthma by age three in the placebo group.
However, among children born to mothers randomized to the treatment arm, there was a
strong effect of initial level, whereby a higher initial level greater than 30 ng/mL conferred
a 58 percent reduced risk for asthma or recurrent wheeze by age three years, compared
with those children born to mothers with an initial level less than 20 ng/mL who received
placebo (adjusted odds ratio 0.42, 95% CI 0.19-0.91).

● A subsequent meta-analysis of the two trials (VDAART and COPSAC2010) also supports the
concept that maternal vitamin D intake is protective for the occurrence of wheeze or
asthma in the offspring up to age three (adjusted OR 0.74; 95% CI, 0.57-0.96) [13],
although analysis of these participants at age six suggests a loss of benefit [23,25]. An
important point is that these trials only performed vitamin D supplementation during the
prenatal phase; no supplementation was undertaken after birth. It remains to be seen
whether additional supplementation during the post-natal phase will add and sustain the
protective effect seen in early life. (See 'Vitamin D in infancy' below.)

A potential mechanism by which early life vitamin D deficiency can increase the risk for asthma
is through immunomodulation of multiple cell types, notably dendritic and T regulatory cells. In
addition, vitamin D has effects on in-utero lung development [28,29]. (See "Vitamin D and
extraskeletal health", section on 'Immune system' and "Vitamin D and extraskeletal health",
section on 'Pregnancy outcomes'.)

Polyunsaturated fatty acids — Observational data suggest that a shift to a Westernized diet
has increased the intake of n-6 (or omega-6) polyunsaturated fatty acids (in particular, linoleic
acid from plant oils) and decreased intake of n-3 (or omega-3) polyunsaturated fatty acids
(particularly, eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA] from oily fish). This
change may be associated with the increase in the incidence of asthma [14,30].

In the COPSAC2010 study described above, separate arms of the trial supplemented women
with 2.4 g per day of n-3 PUFA (55 percent EPA and 37 percent DHA) versus placebo (olive oil).
Children born to mothers in the PUFA arm had a 16.9 percent relative decrease in persistent
wheeze or asthma compared with 23.7 percent in the control group (HR 0.69; 95% CI 0.49-0.97).
The effect was greatest in those women whose levels of EPA and DHA were in the lowest third
of the population at randomization [30].

Other vitamins and minerals — Maternal intakes of the antioxidant nutrients, vitamins E and
C and zinc, may modulate the risk for wheezing and asthma in young children, although further
study is needed [15,16,18,31-34]:

● Vitamin E – In the SEATON cohort, a birth cohort of over 1000 children in Scotland,
maternal total intake (diet plus 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) [31]. 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 [32]. In addition, maternal zinc intake was also inversely associated
with active asthma in the children (adjusted OR 0.72). Follow-up of the SEATON cohort
showed that children born to mothers with higher vitamin E intakes had decreased odds
for asthma by age 10 years (OR 0.89, 95% CI 0.81-0.99) [18].

● Vitamin E and zinc – In an analysis of a birth cohort of over 1000 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 [33].

● Vitamin C – Based on observations that vitamin C supplementation blocked the effects of

in-utero nicotine exposure on primate lung development and infant lung function, two
placebo-controlled clinical trials have been conducted on the impact of vitamin C
supplementation (500 mg/day) on the offspring of smoking pregnant women. Following
studies showing generally encouraging results at earlier timepoints [35-37], long-term
follow-up of the larger of these trials assessed the offspring of over 250 smoking pregnant
women at age four to five years [38]. The children of women who received vitamin C
demonstrated decreased risk of wheezing (28 versus 47 percent; odds ratio 0.41, 95% CI
0.23-0.74) as well as improved lung function (1.45 versus 1.24 L/s forced mid-expiratory
flow [FEF 25 to 75], 95% CI of the difference 0.13-0.21 L/s). Collectively, these studies
 suggest that vitamin C supplementation may mitigate harmful effects of in-utero tobacco
exposure.

Mediterranean diet — Data regarding a reduced risk of wheeze and atopy among offspring
of mothers who adhered to a Mediterranean diet during pregnancy have been mixed [8,39-41].
However, a systematic review and meta-analysis found the reduction in current wheeze
associated with a Mediterranean diet was largely driven by results from Mediterranean centers,
while the reduction in "asthma ever" was independent of the location of the center [8]. The
reason for a greater benefit to the Mediterranean diet in Mediterranean locations is unclear. A
separate study (n = 14,062 children) found no effect of dietary pattern on the development of
asthma after controlling for confounders [40].

Sugar intake — The increase in childhood asthma rates has occurred contemporaneously
with a 25 percent increase in per capita consumption of refined sugars in the United States. The
effect of maternal intake of free sugar (estimated by questionnaire) during pregnancy on
childhood respiratory and atopic outcomes was examined in a large birth cohort in the United
Kingdom [42]. After controlling for a number of confounders including sugar intake by the
child, the likelihood of childhood atopic asthma was increased in the quintile with the highest
sugar consumption compared with the lowest quintile (OR 2.01, 95% CI 1.23-3.29). Additional
study is warranted.

Maternal asthma — Poor maternal asthma control during pregnancy may increase the
likelihood of childhood asthma in the offspring based on results from a prospective population-
based cohort study, underscoring the importance of maintaining asthma control during
pregnancy [43].

Prenatal exposure to maternal smoking — Prenatal exposure to maternal smoking is

associated with reduced pulmonary function in infants and a greater likelihood of childhood
asthma [44-50]. In addition, smoking during gestation is associated with other adverse
pregnancy outcomes, including premature delivery, which increase the risk for asthma. (See
'Prematurity' below and "Cigarette and tobacco products in pregnancy: Impact on pregnancy
and the neonate".)

● One study, for example, evaluated the effect of prenatal maternal cigarette smoking on
the pulmonary function of 80 healthy infants shortly after birth [44]. Maternal smoking
was assessed by questionnaire reports and urine cotinine concentration at each prenatal
visit. Pulmonary function (assessed as flow at functional residual capacity [FRC]) was lower
in infants whose mothers smoked compared with those whose mothers did not smoke.
 ● A study of the effects of prenatal and postnatal exposure to smoking on asthma and
wheezing in children included 620 school children aged seven to nine years with current
asthma or wheeze in the last 12 months and found an association between current
asthma/wheeze and maternal smoking during pregnancy (OR 1.87, 95% CI 1.25-2.81) and
the number of household smokers (OR 1.15, 95% CI 1.01-1.30) in a multivariate logistic
regression analysis [46].

● A separate 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 11,534 school-aged children
in the United States and Canada [47]. Active asthma was significantly associated with
exposure to environmental tobacco smoke in pregnancy only (OR 2.70, 95% CI 1.13-6.45).

● A European birth cohort study of more than 21,000 children examined the effects of
maternal smoking exclusively during pregnancy, during pregnancy and in the first year
after delivery, and exclusively for the first year after delivery [48]. Exposure to maternal
smoking exclusively during pregnancy was associated with wheeze or asthma at four to
six years of age, with odds ratios of 1.39 (95% CI 1.08-1.77) and 1.65 (95% CI 1.18-2.31),
respectively. In comparison, children exposed to maternal smoking just during the first
year of life, but not during pregnancy, did not have an increased risk of wheeze or asthma.

It appears likely that vitamin C supplementation can mitigate some of the deleterious effects of
smoking on the developing lung. (See 'Other vitamins and minerals' above.)

Prenatal medication exposure — Use of certain medications (eg, acetaminophen, acid

suppressive medications, and antibiotics) has been associated with childhood asthma, but often
results vary among studies and causality has not been proven.

Acetaminophen — Prenatal acetaminophen exposure has been associated with an increase in

the risk of early childhood asthma, although results vary among studies [49,51-53]. In a
longitudinal study of 1490 mother-child pairs, structured interviews during pregnancy and
questionnaires at 6 and 12 months postpartum were used to characterize acetaminophen use
during pregnancy and infancy and also exposure to potential confounders [51]. Prenatal
acetaminophen was associated with increased asthma (OR, 1.26; 95% CI 1.02-1.58) at age 3 to 5,
but not at age 7 to 10. Infant acetaminophen use is discussed separately. (See 'Acetaminophen'
below.)

Acid suppressive medications — The use of acid suppressive medications during pregnancy
has been variably associated with an increased risk of childhood asthma in the offspring [54-
58]. Given the risk of potential confounders, further research is needed to determine if this
association is causal [59].

● In a systematic review and meta-analysis of population-based observational studies,

maternal use of acid suppressive medication (histamine H2 blocker or proton pump
inhibitor) during pregnancy was associated with an increased risk of childhood asthma in
the offspring compared with no use (relative risk [RR] 1.45, 95% CI 1.35-1.56), with similar
risk between the two types of agents [57].

● In a separate systematic review and meta-analysis of retrospective cohort and case-control

studies, maternal use of acid suppressive medication (histamine H2 blocker or proton
pump inhibitor [PPI]) during pregnancy was associated with an increased risk of asthma in
the offspring compared with no use (RR 1.36, 95% CI 1.16-1.61) [60].

● In contrast, the Health Improvement Network study of 2371 prenatally exposed and 7745
unexposed infants found no association between asthma and prenatal exposure to PPIs
and a small increase in risk after H2 blocker exposure that was largely explained by
maternal comorbidities [58].

Antibiotics — Prenatal antibiotic exposure is associated with a dose-dependent increase in

asthma risk depending on the number of courses of antibiotics [61]. However, maternal
antibiotic use before and after pregnancy conferred a similar risk, suggesting that the
association is not causal.

Perinatal factors

Prematurity — Prematurity is the most important and consistent perinatal risk factor for
asthma [62-69]. Numerous observational studies have demonstrated this association, examples
of which include the following:

● In a study that used the Swedish Medical Birth Register (over four million children born
from 1973-2013) and multiple nationwide medical registries, over 600,000 persons with
asthma were identified [69]. Preterm birth (before 36 weeks) was associated with
increased risk of asthma in childhood, adolescence, and adulthood (HR 1.73, 1.29, and
1.19, respectively) even after adjustment for birth year, sex, maternal smoking and BMI,
and parental age, education status, and asthma. Earlier prematurity demonstrated a
higher risk of subsequent asthma compared with full-term birth: HR 3.0 (95% CI 2.9-3.2)
for those born at 22 to 27 weeks; HR 1.76 (95% CI 1.7-1.8) for those born at 28 to 33 weeks;
and HR 1.31 (95% CI 1.29-1.32) for those born at 34 to 36 weeks gestation. Persons with
preterm birth and known perinatal respiratory complications (n = 1391) had a modestly
 increased risk of developing asthma (HR 2.1, 95% CI 1.7-2.5) compared with those without
such complications (HR 1.43, 95% CI 1.41-1.44). Neither familial factors nor cause of
preterm birth (spontaneous versus medically indicated) contributed significantly to the
risk. Bronchopulmonary dysplasia was very rare in this cohort (n = 458). The authors
concluded that impaired lung development in preterm infants, even those without early
respiratory complications, increases long-term risk of asthma.

● A separate report 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 9 to 11 years [63]. The
prevalence of asthma was significantly increased in premature female children (OR 2.6),
particularly in those who required mechanical ventilation after birth (OR 3.7). No such
difference could be demonstrated for male children.

● Prematurity was a significant risk factor for both recurrent wheezy bronchitis and asthma
in a second cross-sectional study of 1812 primary school children [64].

Pre-eclampsia — A report from the COPSAC2010 study in Denmark suggests that pre-
eclampsia in the mother may be a risk factor for childhood asthma (treatment with inhaled
glucocorticoids at age seven years) in the offspring (adjusted OR 4.01, 95% CI 1.11-14.43), as
well as eczema and allergy [70]. Maternal asthma increased the risk of pre-eclampsia.

Mode of delivery — Cesarean delivery may increase the risk of childhood asthma compared
with vaginal delivery [71-77]. A population-based cohort study of 1.7 million singleton births
found an increased risk of childhood asthma with both planned and emergency cesarean
delivery (HR 1.52, 95% CI 1.42-1.62) [75]. One possible explanation is that neonates born by
vaginal delivery acquire most of their intestinal flora by exposure to 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 [71-74,77-87]. (See "Increasing prevalence of asthma and allergic rhinitis and the
role of environmental factors", section on 'Improved hygiene'.)

A small study found that children born by Cesarean delivery had increased levels of interleukin
(IL)-13 and interferon (IFN)-gamma compared with children born vaginally [86]. Increased levels
of these cytokines have been associated with the subsequent development of asthma and
allergies.
 Neonatal jaundice — The potential role of neonatal jaundice as a risk factor for childhood
asthma was examined in a study of 11,321 children in the National Health Insurance Database
in Taiwan [88]. After adjustment for confounding factors (eg, prematurity, low birth weight), the
rate of asthma was higher in children with neonatal jaundice than those without (OR 1.64, 95%
CI 1.36 to 1.98).

Breastfeeding — Breastfeeding appears to be associated with a lowered incidence of

recurrent wheezing during the first two years of life, possibly reflecting fewer respiratory virus
infections. Breastfeeding does not clearly reduce wheezing in later childhood, which is more
likely to represent atopic asthma. This topic is reviewed in detail separately. (See "The impact of
breastfeeding on the development of allergic disease".)

Vitamin D in infancy — Aside from prenatal vitamin D supplementation (see 'Vitamin D'
above), investigators have also examined postnatal supplementation. In a trial among 300
premature (28 to 37 weeks) infants of African descent, sustained supplementation (400
international units/day cholecalciferol through six months of age) was compared with placebo
(diet-limited supplementation) [89]. The children in the sustained supplementation arm had
lower risk for recurrent wheezing by 12 months (RR 0.66, 95%CI 0.47-0.94). While early recurrent
wheeze is not asthma, this represents a risk for developing asthma. This study suggests that
postnatal supplementation with vitamin D could play a role in asthma prevention, but further
follow-up of the children is necessary to determine whether the effect is sustained beyond the
first year of life. What remains unclear is whether sustained supplementation both during
pregnancy and during infancy will lead to better preventive effects on asthma and recurrent
wheeze. (See "Vitamin D insufficiency and deficiency in children and adolescents", section on
'Prevention in the perinatal period and in infants'.)

CHILDHOOD

Sex — Childhood asthma tends to be a predominantly male disease, with the relative male
predominance being maximal at puberty [90,91]. After age 20, the prevalence is approximately
equal between males and females until age 40, when the disease becomes more common in
females [92]. (See "Natural history of asthma".)

Reasons for sex-related differences are unclear and largely unexplored. Possible explanations
include:

● The greater prevalence of atopy (ie, evidence of immunoglobulin E [IgE] sensitization to

allergens) in young males.
 ● Reduced relative airway size in males compared with females [93]. Smaller airway size may
also contribute to the increased risk of wheezing after viral respiratory infections in young
males compared with females. (See "Role of viruses in wheezing and asthma: An
overview".)

● Differences in symptom reporting between male and female children [94].

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 [95]. 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 (OR) between 1.58 and 2.18,
depending on the measurement examined.

Airway hyperresponsiveness — 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. AHR is a risk factor for the
development of asthma, but not all individuals with AHR will develop asthma [96,97]. (See
"Asthma in adolescents and adults: Evaluation and diagnosis".)

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 [90]. Moreover, 20 to 50 percent
of subjects with airway hyperresponsiveness are asymptomatic at the time of testing. (See
"Bronchoprovocation testing".)

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 [98]. 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 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 sex, 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 [99]. 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 with only 2 of 88 (2 percent) in the control
group. The severity of AHR appeared to predict which subjects would become asthmatic.

Atopy and allergens — Atopy, the genetic predilection to produce specific IgE following
exposure to allergens, and sensitization, the development of allergen-specific IgE following
exposure, are prerequisites for the development of allergic disease. The association between
asthma and other atopic conditions (eg, allergic rhinitis) is well-documented, although
sensitized individuals do not necessarily develop allergic disease. A growing body of research
suggests that the early life microbiome likely influences the likelihood that an allergic
predisposition results in asthma. (See "The relationship between IgE and allergic disease".)

Atopy — Serum levels of IgE appear to be closely linked with airway hyperresponsiveness,
whether or not asthma symptoms are present [100-103]. 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.

Immunoglobulin E — Analysis of infant cord blood and serum IgE levels in childhood
suggests that atopic disease generally, and asthma in particular, correlate with serum IgE,
although the predictive value of elevated levels is low at an individual level.

● Cord blood IgE – 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
[104,105]. 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 [106]. The
interrelationship of these factors requires further study, although it suggests that both
genetic and environmental factors influence the atopic diathesis, even before birth.

● Total serum IgE – 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 [102]. 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 from a birth cohort of 1037 New
Zealand children, who had serum IgE levels measured [103]. 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, such that AHR was present in 30 percent of individuals with an IgE level >315
international units/mL.

Allergen skin test positivity — 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 [100]. The association between wheeze and atopy was
increased in countries with higher economic development.

The Third National Health and Nutrition Examination Survey (NHANES III), which performed
skin testing in 12,106 subjects age 6 to 59 years, found that half of the asthma cases were
attributable to atopy (at least one positive skin test) [101].

Allergen exposure — A consensus is emerging that indoor allergens (eg, dust mite, animal
proteins, cockroach, and fungi) play a significant role in the development of asthma and
recurrent wheeze in children [107-111]. However, it has been difficult to demonstrate a
causative relationship, and the majority of these studies were performed on high-risk groups.
At least one prospective study of allergen exposure in early childhood, carried out in a cohort
from the general population, found that a minimum threshold level of allergen was necessary
for sensitization or asthma to develop, but there was no dose-response relationship above that
level [112].

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 [113]. 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. (See "Increasing
prevalence of asthma and allergic rhinitis and the role of environmental factors".)

Sources of indoor allergens include house dust mites, animal proteins (eg, mouse, 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 [107,114].

● 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 and 90
percent of cases among children and young adults [97,107,115].

● Indoor fungi – Sensitization and exposure to indoor fungi (eg, Penicillium, Aspergillus, and
Cladosporium species) appears to be important for the development of asthma [116,117].
Alternaria is a potent outdoor aeroallergen that can colonize indoor environments, but
studies are mixed about whether indoor exposure to Alternaria is associated with an
increased risk of asthma [117,118].

● Cockroach allergen – In studies of urban asthma, sensitization to cockroach allergen has

been shown to be a significant risk factor in the development of asthma [119,120]. In
addition, morbidity from asthma in children from urban areas is associated with the
presence of cockroach allergy and exposure to high levels of cockroach allergen in
bedroom dust [121].

● Indoor animals – Early life exposure to indoor cat and dog allergens has been found to be
both associated with and protective against the development of asthma [111,122,123]. 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 [123]. (See "Pets in the home: Impact on
allergic disease".)

● 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 and the role
of environmental factors", section on 'Since 1960'.)

Methods to reduce exposure to these allergens are discussed separately. (See "Allergen
avoidance in the treatment of asthma and allergic rhinitis".)

Influence of microbiome — Exposure to bacteria and bacterial products may influence the
development of allergen sensitization and asthma, although the exact effects appear to depend
on a complex interplay of timing of exposure (first year of life versus later in life), location,
abundance and diversity of the microbiome, and specific microbial products [124-126]. As an
example, early life exposure to allergen and certain bacteria in the environment may lower the
risk of asthma [127], while later life exposure to bacteria may increase the risk of asthma. (See
"Increasing prevalence of asthma and allergic rhinitis and the role of environmental factors".)

Observations from the Urban Environment and Childhood Asthma study, which assessed
allergen and bacterial exposures nested case-control study of 104 children in a birth cohort at
high risk of asthma, suggest that the effect of early life allergen exposures may differ from
cumulative allergen exposure and the combination of high-level allergen and bacterial
exposure in early-life may be protective against allergen sensitization and recurrent wheeze
[111]. Accumulated allergen exposure (cockroach, cat, and mouse) over the first three years of
life was associated with increased allergic sensitization (based on serum IgE) and, in turn, with
recurrent wheeze. In contrast, exposure to these same allergens in the first year was negatively
associated with recurrent wheeze. Moreover, the combination of early-life allergen exposure
plus high-level exposure to bacteria in house dust was associated with a further reduction in
risk of recurrent wheeze by age three. The mechanism for this protective effect is not known,
but changes in gut microflora and related effects on innate immunity are hypothesized.

Levels of endotoxin, an inflammatory lipopolysaccharide cell wall constituent of gram-negative

bacteria, reflect the degree of microbial exposure. In addition, endotoxin may have a direct
immunomodulatory effect. Determinants of endotoxin levels 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 (greater bacterial exposure) and diagnosed asthma, asthma symptoms in the past year,
current use of asthma medications, and wheezing [128]. The effect of farm animal exposure on
asthma prevalence is discussed separately. (See "Increasing prevalence of asthma and allergic
rhinitis and the role of environmental factors", section on 'Farms, villages, worms, and other
parasites'.)

Respiratory infections — Viral and bacterial respiratory infections are well-known triggers of
asthma exacerbations in children and adults [129,130]. Whether respiratory infections are a
cause of asthma, a marker of susceptibility for asthma, or a protective factor remains unclear
[131,132]. It may be that the effect of infection depends on the specific type and number of
infections, genetic susceptibility, and other factors such as age, atopic status, and the
individual's microbiome.

Viral respiratory tract infections in infancy, particularly respiratory syncytial virus (RSV) and
human rhinovirus (HRV), are predictive of the development of asthma in later childhood to
young adulthood, although a causal effect has not been demonstrated. The effect of viral
infections on asthma and wheezing is discussed separately. (See "Role of viruses in wheezing
and asthma: An overview" and "Increasing prevalence of asthma and allergic rhinitis and the
role of environmental factors", section on 'Improved hygiene'.)

Mycoplasma pneumoniae infection was associated with the subsequent development of asthma
in a study of 1591 Taiwanese adults and children [133]. The diagnosis of M pneumoniae was
made based on serologic studies, and the risk of incident asthma was compared with a
frequency matched sample of 6364 patients without infection. The adjusted hazard ratio for
asthma was 3.35 (95% CI 2.71-4.15) for the M pneumoniae cohort and was higher in the first two
years following M pneumoniae infection (AHR 4.41; 95% CI 3.40-5.74).

Medication use in infancy — Epidemiologic studies have found associations between the
development of asthma and maternal and infant use of acetaminophen and ibuprofen and also
infant intake of antibiotics. However, these studies have inadequately accounted for
confounding bias. 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,
which could lead to oxidative damage, increased production of prostaglandin E2, and
promotion of T helper lymphocyte (Th2) processes [134-141]. However, systematic reviews and
prospective studies have concluded that acetaminophen use in infancy is unlikely to increase
the risk of developing asthma.

Initial studies that suggested a relationship between acetaminophen use in childhood and
asthma were likely subject to recall bias and confounding by indication [142-148]. Recall bias
can be problematic for retrospective studies; caregivers of a child with asthma may be more
likely to recall acetaminophen use than caregivers of a healthy child [149,150]. Confounding by
indication can be a problem when evaluating over-the-counter medications such as
acetaminophen when the indication for the medication (eg, respiratory infection) could be
contributing to the risk of asthma.

Examples of studies that controlled for recall and confounding bias include the following:

● In a longitudinal study of 1490 mother-child pairs with structured interviews during

pregnancy, unadjusted models showed increased asthma risk in early childhood with
higher infant acetaminophen use, but controlling for respiratory tract infections
attenuated the risk estimate (OR 1.03; 95% CI 0.88-1.22) [51].

● 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 [151]. After adjustment for the frequency of
 respiratory infections, the association between paracetamol use and caregivers report of
asthma at age six or seven disappeared. Paracetamol use for nonrespiratory indications
was not associated with asthma.

● 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 after controlling for respiratory infection [152].

● The Acetaminophen Versus Ibuprofen in Children with Asthma trial (AVICA;

ClinicalTrials.gov Identifier: NCT01606319), which compared the effects of acetaminophen
versus ibuprofen on asthma exacerbations in young children with asthma, is described in
the next section. (See 'Ibuprofen' below.)

Ibuprofen — Few studies have examined the potential effect of maternal or infant ibuprofen
use on development of asthma. Similar to studies of acetaminophen use, the potential risk of
asthma associated with ibuprofen is largely attenuated after adjustment for respiratory
infections.

● In the longitudinal study of 1490 mother-child pairs mentioned above, a small increased
risk of asthma in early childhood (three to five years) was associated with early life intake
of ibuprofen (OR, 1.19; 95% CI 1.05-1.36), after adjustment for respiratory tract infections
[51]. By 7 to 10 years, the association was no longer notable.

● The AVICA trial that compared acetaminophen versus ibuprofen for the alleviation of fever
or pain in young children (12 to 59 months) with asthma showed no differences in the
number of asthma exacerbations over 46 weeks between children randomized to either
medication arm [153]. The mean exacerbation number in children in the acetaminophen
arm was 0.81 per participant and in children in the ibuprofen arm was 0.87 per participant
(relative rate of asthma exacerbations in the acetaminophen group versus the ibuprofen
group was 0.94, 95% CI 0.69-1.28). While this trial provides data that either of these
medications, in usual doses, for the relief of fever or pain in young children will not lead to
worsening of existing asthma, the question remains whether the use of these
medications, either in pregnancy or early childhood, confers increased risk for the
development of asthma. However, a true placebo-controlled trial would probably never be
done for practical and ethical reasons.

Antibiotics — Exposure to antibiotics during infancy was associated with the development of
asthma in later childhood in retrospective studies, but the association did not reach significance
in prospective studies [154-157]. The "microflora hypothesis," or the dependency of the
neonatal gut on the presence of normal microflora for the development of tolerance in early
life, was postulated to be a potential mechanism.

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 with unexposed infants (OR 2.05, 95% CI 1.41-2.99) [155].
However, 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 (OR 2.82, 95% CI 2.07-3.85)
than in the prospective studies (OR 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.

Air pollution

Outdoor — A growing body of evidence suggests that early-life exposure to air pollution
increases the risk of pediatric asthma, in addition to the known correlation between levels of air
pollution and lung disease in general [158-165]. Results vary among studies, and it is possible
that asthma is related to specific pollutants (eg, nitrogen dioxide, carbon monoxide, sulfur
dioxide, fine particulate matter), while other respiratory diseases are related to total air
pollution.

● Nitrogen dioxide – In a longitudinal study of 4140 children, decreasing nitrogen dioxide

(NO2) concentrations were associated with a reduction in childhood asthma incidence
[166]. No association was found between levels of ozone and particulate matter <10
micrometer and asthma incidence.

● Sulfur dioxide versus NO2 – Studies in reunified Germany have provided data on two
populations exposed to different levels of pollutants [113,167]. East Germany had
consistently high levels of sulphur dioxide (SO2) and other particulates, whereas West
Germany had low levels of SO2 but slightly higher levels of 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 [113,167].

● Proximity to roadway – In a birth cohort study (1522 children), residence in proximity to a

major roadway even at relatively low levels of traffic-related pollution increased the risk of
early childhood asthma [162]. Similar findings regarding traffic-related air pollution were
reported in a separate study of 2023 children in Mexico; parental asthma or allergies
enhanced the effect [163].
 An eight year prospective study found an association between the risk of asthma onset
and both greater exposure to NO2 and living in close proximity to a major road [168].

● Mixed pollutants – 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 [169]. 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.

Indoor — Contributors to indoor air pollution include products of combustion from gas-fired
appliances and indoor fires (eg, NO2, particulates) [170], environmental tobacco smoke [171],
and volatile organic compounds (eg, formaldehyde).

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 [170]. 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) [170]. 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.

The use of open fires for indoor cooking is associated with increased prevalence of asthma and
increased risk of symptoms [172-174]. In a multivariate analysis of data from ISAAC, sole use of
an open fire for cooking was associated with wheeze in the past year (OR 2.17, 95% CI 1.64-2.87)
for children aged six to seven years and (OR 1.35, 95% CI 1.11-1.64) for children aged 13 to 14
years [172].

Among children, exposure to poor indoor air quality in schools is associated with an increased
prevalence of asthma [175].

Obesity — An increased prevalence of asthma is reported among obese children with a dose-
dependent effect of body mass index (BMI) on asthma risk [176]. The relationship between
obesity and asthma is discussed separately. (See "Obesity and asthma", section on
'Epidemiology'.)

Early puberty — Earlier puberty is associated with an increased risk of developing asthma in
young adulthood [177-179]. It is possible that increased BMI contributes to the effect on
asthma risk by promoting early puberty. A trend towards earlier puberty has been observed
worldwide.
 ● A large databank study that used genetic variants known to affect age at puberty found
that early puberty among females was associated with an 8 percent increase in risk of
asthma (OR 1.08; 95% CI 1.04-1.12), compared with an 8 percent decrease in risk with late
menarche (OR 0.92; 95% CI 0.89-0.97) [179]. Similar effects were noted with early versus
late puberty among males, but with broader confidence intervals.

● 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 [177]. 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 BMI, age, height, education,
and smoking status did not alter these findings.

ADOLESCENCE AND ADULTHOOD

Studies of patients with onset of asthma in adulthood have found an association of asthma with
obesity, active and passive tobacco smoke exposure, certain occupational exposures, chronic
rhinitis, and hormone replacement therapy.

Obesity — Age-adjusted prevalence rates for asthma and obesity are increasing in the United
States. Several lines of evidence suggest that adults with an elevated body mass index (BMI) are
at increased risk of asthma [180-187]. This risk may be greater for nonallergic asthma than
allergic asthma [188]. (See "Obesity and asthma".)

However, it is possible that the magnitude of this risk is overstated [189-194]. 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 [193]. Thus, although
obesity is statistically associated with asthma, biologic causality has not been proven.

Tobacco smoke — Population-based studies appear to show a relationship between smoking

and airway hyperresponsiveness [90]. Studies have also provided evidence for an association
between smoke exposure and asthma development.

Active smoking — Several studies have demonstrated that active smoking increases the risk
for developing asthma [195-198].
 ● The largest and longest study, the Black Women's Health Study, followed 46,182
participants for 16 years, during which 1523 women reported incident asthma [198]. The
hazard ratios (HR) for adult-onset asthma among former smokers and active smokers
were 1.36 (95% CI 1.11-1.67) and 1.43 (95% CI 1.15-1.77), respectively, compared with no
active/passive smoking exposure.

● A 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
[195]. 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 (odds ratio [OR] 4.42, 95% CI 3.31-5.92) after controlling for a variety of
factors, including sex, 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 (95% CI 1.7-8.5) for developing asthma, compared with nonsmoking
peers [196]. Other environmental exposures may synergistically increase the risk of
asthma associated with tobacco exposure; as an example, one study in over 2300
adolescents showed a heightened risk of asthma with exposure to tobacco and water
disinfection byproducts relative to either exposure alone [199].

Secondhand smoke — A number of studies suggest that secondhand smoke exposure is

associated with the development of asthma [114,123,198,200-203]. Maternal smoking is the
most important cause of secondhand smoke exposure, because of the typically greater
exposure of the child to the mother than other caregivers [114]. 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 [200]. Similar findings were noted
in another study in which the effect of maternal smoking was found in mothers of low
educational level [201]. (See "Secondhand smoke exposure: Effects in children".)

In adults, data on the effects of environmental tobacco exposure also suggest an increased risk
of nonmalignant lung disease. In the Black Women's Health Study noted above, the HR for
adult-onset asthma among nonsmokers with passive smoking exposure was 1.21 (95% CI 1.00-
1.45) compared with no smoke exposure [198]. The association between passive exposure to
tobacco smoke and respiratory symptoms was also 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)
[202]. Passive exposure to tobacco smoke was associated with increases in the risks of doctor-
diagnosed asthma (OR 1.39), wheezing, bronchitis, and dyspnea.

Occupational exposures — The European Community Respiratory Health Surveys (ECRHS and
ECRHS-II) has identified several occupations that are associated with an increased risk of new
onset asthma; nursing and cleaning were responsible for the most cases [204]. Inhalational
accidents (eg, fires, mixing cleaning agents, industrial spills) were also associated with an
increased risk of new onset asthma. (See "Occupational asthma: Definitions, epidemiology,
causes, and risk factors".)

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 [205].

Rhinitis — Adults with rhinitis are at greater risk than those without rhinitis for developing
adult-onset asthma [206-208]. This was best demonstrated in a prospective multicenter study of
6461 adults, aged 20 to 44 years [209]. Subjects were randomly chosen from the general
population, and a cohort without asthma was evaluated with questionnaires, allergen skin
testing, serum specific and total immunoglobulin E (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% CI 2.1-5.9) and for non-
allergic rhinitis, 2.1 (CI 1.6-4.5), after controlling for country of origin, sex, forced expiratory
volume in one second (FEV1), total IgE, family history of asthma, baseline age, BMI, respiratory
infections in childhood, and smoking.

Postmenopausal hormone replacement therapy — Observational studies have reported a

modest increase in the incidence of asthma among postmenopausal women taking hormone
replacement therapy [92,210-214]. 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 [214].
SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Asthma in adolescents
and adults".)

SUMMARY AND RECOMMENDATIONS

● Prenatal and perinatal factors – Several prenatal and perinatal factors (eg, maternal age,
smoking, diet, and medication use) have been implicated in the development of childhood
asthma, although data are conflicting. (See 'Pre- and perinatal factors' above and 'Prenatal
exposure to maternal smoking' above.)

• Accumulating evidence suggests a relationship between maternal vitamin D deficiency

and the risk of childhood asthma. High-dose vitamin D supplementation during
pregnancy appears to reduce the risk of early life wheeze/asthma, but not long-term
asthma, in the offspring. (See 'Vitamin D' above and "Management of asthma during
pregnancy", section on 'High-dose vitamin D'.)

• Active smoking and exposure to environmental tobacco smoke (particularly maternal)

appear to increase the risk of developing asthma. However, this is difficult to prove in
cross-sectional studies as patients with known asthma are less likely to start smoking.
Providing vitamin C supplementation (500 mg/day) to smoking pregnant women may
improve early childhood wheezing and pulmonary function. (See 'Prenatal exposure to
maternal smoking' above and 'Other vitamins and minerals' above.)

• Maternal and early childhood use of certain medications (eg, acetaminophen, acid
suppressive medications, and antibiotics) has been associated with childhood asthma,
but often results vary among studies and causality has not been proven. (See 'Prenatal
medication exposure' above and 'Medication use in infancy' above.)

● Childhood risk factors

• Childhood asthma affects males more than females. The incidence in females begins to
rise at puberty, and by early adulthood, the prevalence is about equal. By age 40, more
women than men have asthma. The reason for early male-sex predominance is
unknown (See 'Sex' above.)
 • Lower lung function measured shortly after birth is associated with subsequent
development of asthma. Airway hyperresponsiveness (AHR), the exaggerated response
of asthmatic airways to noxious stimuli, is often detectable before symptoms of asthma
develop, but not everyone with AHR develops asthma. (See 'Early abnormalities in
pulmonary function' above.)

• Asthma is more commonly present in individuals with other atopic diseases, such as
atopic dermatitis and allergic rhinitis; although only approximately one-third of
children with atopic dermatitis will go on to develop asthma. Increased total serum
levels of immunoglobulin E (IgE) are associated with AHR. Sensitization to indoor
allergens is strongly associated with asthma, although allergen exposure does not
necessarily increase the risk for developing asthma. (See 'Atopy and allergens' above.)

• Exposure to bacteria and bacterial products may influence the development of allergen
sensitization and asthma, although the exact effects appear to depend on the timing of
exposure (first year of life versus later in life). The exact mechanism for these effects
remains unclear. (See 'Influence of microbiome' above.)

● Adolescent and adult risk factors – Tobacco smoke exposure, occupational exposure to
noxious aerosols, and allergic rhinitis have strong associations with asthma development
in adolescents and adults. Patients with an increased body mass index (BMI) have a
greater risk of developing asthma than those with a normal BMI, although the magnitude
of the effect is unclear. (See 'Tobacco smoke' above and 'Occupational exposures' above
and 'Rhinitis' above and 'Obesity' above.)

Use of UpToDate is subject to the Terms of Use.

Topic 572 Version 57.0