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Special Features: Asthma |

The Poorly Explored Impact of Uncontrolled AsthmaUncontrolled Asthma FREE TO VIEW

Paul M. O’Byrne, MBBCh, FCCP; Søren Pedersen, MD; Michael Schatz, MD, FCCP; Anders Thoren, PhD; Ella Ekholm, PhD; Lars-Göran Carlsson, MD; William W. Busse, MD
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From the Firestone Institute of Respiratory Health (Dr O'Byrne), St. Joseph's Healthcare and Department of Medicine, McMaster University, Hamilton, ON, Canada; University of Southern Denmark (Dr Pedersen), Paediatric Research Unit, Kolding Sygehus, Kolding, Denmark; Department of Allergy (Dr Schatz), San Diego Medical Center/Kaiser Foundation Hospital, San Diego, CA; Research and Development (Drs Thoren, Ekholm, and Carlsson), AstraZeneca Lund, Sweden; and Department of Medicine (Dr Busse), University of Wisconsin Hospitals and Clinics Authority, Madison, WI.

Correspondence to: Paul M. O’Byrne, MBBCh, FCCP, Firestone Institute of Respiratory Health, St. Joseph’s Healthcare and Department of Medicine, McMaster University, 1200 Mian St W, Hamilton, ON, L8N 3Z5, Canada; e-mail: obyrnep@mcmaster.ca


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2013;143(2):511-523. doi:10.1378/chest.12-0412
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The goal of asthma management is to achieve disease control; however, despite the availability of effective and safe medications, for many patients asthma remains uncontrolled. One reason for this is the fear of long-term side effects from the regular use of inhaled corticosteroids (ICSs). Adverse effects of poorly controlled asthma (for example, obesity, pneumonia, and risks to the fetus) can be perceived as side effects of ICSs. Poorly controlled asthma adversely affects children’s cardiovascular fitness, while children with well-controlled asthma perform at the same level as their peers. Children with uncontrolled asthma also have a higher frequency of obesity than children with controlled asthma. Stress can affect asthma control, and children with poorly controlled asthma are more likely to have learning disabilities compared with those with good control. In adults, focused attention and concentration are negatively affected in patients with untreated asthma, and patients with asthma are at greater risk for depression. Also, poorly controlled asthma increases the risks of severe asthma exacerbations following upper respiratory and pneumococcal pulmonary infections. ICSs used to improve asthma control have been demonstrated to improve all of these outcomes. Lastly, the risks of uncontrolled asthma during pregnancy are substantially greater than the risks of recommended asthma medications. Treatments to maintain asthma control are the best approach to optimize maternal and fetal health in the pregnancies of women with asthma. The maintenance of asthma control has significant advantages to patients and greatly outweighs the potential risks of treatment side effects.

Figures in this Article

Asthma treatment guidelines have identified that the primary goal of management is to achieve overall asthma control.13 This consists of two domains: The first is current asthma control, which includes the day-to-day minimization of both daytime and nighttime symptoms, no activity limitation, minimal rescue bronchodilator use, and no airway narrowing. The second domain includes minimizing the future risks to the patient of developing instability of their control, having severe asthma exacerbations, losing lung function over time, or experiencing side effects from their medications.

The benefits of good asthma control have been well studied and include reduced health-care resource utilization and loss of work/school days, higher probability of a normal quality of life, and reduced risk of exacerbations compared with poorly controlled asthma.4 However, poor asthma control may be associated with other less well-known impacts on the lives of patients. In addition, adverse effects of poorly controlled asthma (for example, obesity, pneumonia, and risks to the fetus) can be perceived as side effects of inhaled corticosteroids (ICSs)—the most effective medications used to achieve asthma control—because of the well-recognized association of these unwanted effects with oral corticosteroid use. The purpose of this review is to highlight some important, but less well-known, consequences of poor asthma control and the effects of maintenance treatment with ICSs on these. Specifically, information will be presented concerning the negative effects of poorly controlled asthma on physical activity and obesity, on cognitive function and educational achievement, on stress and mental health, on pneumonia risk, and on pregnancy and fetal outcomes.

There are significant associations between daily physical activity and cardiovascular fitness in adults as well as children,5 although the associations are weaker in children. In childhood and adolescence, physical activity and/or a high cardiovascular fitness reduce the risk of being overweight.6 Moreover, a significant dose-response relationship has been documented between physical activity/cardiovascular fitness and important risk factors for cardiovascular disease.7 Any increase in daily physical activity is normally considered beneficial. Also, since many patients with asthma experience exercise-induced bronchoconstriction, poorly controlled asthma could have important negative influences on the patient’s daily physical activity, fitness, and risk of obesity.

Several studies have compared physical activity and/or cardiovascular fitness in children with asthma to healthy age-matched and sex-matched children. The results and conclusions vary substantially, and the findings in these studies are difficult to compare due to marked variations in methodology, populations (asthma severity), study design, power, and asthma-diagnosis criteria. The majority of these studies are of cross-sectional design and lack a thorough assessment of the level of asthma control. Thus, while some studies do not find any differences in the daily physical activity or cardiovascular fitness between groups of children with asthma and healthy children,8,9 several do find significantly reduced levels of physical activity or fitness in children with asthma compared with healthy children.1012 The poor characterization of level of asthma control, the treatments used, and even the diagnostic criteria for asthma in most studies preclude an accurate analysis of the reason for this discrepancy. However, two recent studies have assessed the importance of the level of asthma control and fitness, and the amount and intensity of daily physical activity, in a population of well-characterized children with asthma.13,14 Children with asthma were found to be less fit, run shorter distances during exercise tests, have a higher BMI, and a higher percentage of body fat than their healthy control subjects, but no differences were found between the two groups in overall daily activity.13,14 However, within the asthma group, fitness and time spent in intensive daily activity depended significantly on the level of asthma control; children with poorly controlled asthma were less fit and had less intensive daily activity. Moreover, the activity of children with uncontrolled asthma was significantly less than the activity in their healthy control subjects. Similar findings have been reported in younger children.15

When the children with asthma were treated according to guideline recommendations, their asthma control improved during the year of treatment.13,14 The improvements in asthma control were associated with significantly greater improvements in physical activity in children with asthma than in their healthy control subjects (around 3 h per week, of which 33 min were in moderate vigorous activity) (Fig 1). Moreover, the increase in activity was associated with a significantly greater increase in cardiovascular fitness in the asthma group, indicating that the magnitude of the changes in activity was clinically important. The greatest improvements in daily activity and fitness were seen in the children with the poorest asthma control at baseline and greatest improvements in control during treatment. There are no similar studies of the effects of poor asthma control on physical activity and the benefits of improving asthma control on these parameters in adult patients with asthma. In conclusion, uncontrolled asthma adversely affects the daily activity and fitness in children, and long-term treatment both controls asthma and reverses these negative effects of the disease.

Figure Jump LinkFigure 1. A, B, Changes from baseline in time spent in (A) total daily activity and (B) vigorous daily activity in children with asthma and their age-matched and sex-matched healthy control subjects during 1 year of guideline-recommended treatment of the patients with asthma. Improvement of asthma control was associated with statistically significant improvements in daily physical activity compared with the control children. C, Before treatment, children with asthma were less fit than their healthy control subjects. D, But their fitness improved significantly more than the fitness of the healthy children when the asthma was treated. The greatest improvements in daily activity and fitness were seen in the children with the poorest asthma control at baseline and greatest improvements in control during treatment. V˙ O2max = maximum oxygen consumption. (Data derived from Vahlkvist and Pedersen14 and Brasholt et al.15)Grahic Jump Location

Studies have described a significant relationship between physical activity and body fat in healthy children,16 but they do not allow any cause-effect assessment. However, other longitudinal studies have found daily physical activity to protect against accumulation of body fat.1719 The correlation between activity and obesity has generally been low to moderate, probably because many other factors are linked to obesity.

Cross-sectional studies have consistently found an association between asthma and obesity. The relation is often explained by reverse causality, that is, asthma leads to obesity through a more sedentary lifestyle. However, several longitudinal studies20,21 have reported that obesity precedes asthma, suggesting that obesity may be a risk factor for asthma development. Since asthma is often underdiagnosed for some years, it cannot be excluded that an undiagnosed and uncontrolled asthma may have contributed to less physical activity and an increase in weight gain up until the time the diagnosis was finally made. Unfortunately, most studies have quite loose criteria for asthma diagnosis. Since obesity in and of itself may result in symptoms similar to those seen in asthma (dyspnea and reduced physical capability), a lack of strict objective criteria for the diagnosis may also have led to a detection bias contributing to a higher prevalence of obesity.22,23 Finally, airway inflammation and airway hyperresponsiveness are not consistently increased in obese patients with asthma.24,25 Therefore, the relationship between obesity and the development of asthma remains uncertain.

Only two studies have included a careful assessment of the level of asthma control on obesity.13,14 Children with newly diagnosed asthma had a significantly higher BMI and percentage of body fat, as well as a higher frequency of obesity than their healthy control subjects. These parameters were also higher in children with uncontrolled asthma than the values measured in children with well-controlled asthma, but the difference was not statistically significant.14 When treated, asthma became controlled in virtually all children and their annual weight gain was similar to the weight gain in healthy children.15 These results corroborate the findings in healthy subjects that daily physical activity protects against accumulation of body fat,1719 and suggest that improved asthma control allows for improved physical fitness and less risk of obesity.

In conclusion, poorly controlled asthma is more common in patients who are obese. It is difficult to establish what is cause and what is effect; however, uncontrolled asthma is associated with children with a higher percentage of body fat. Children with improved control resulted in normal annual weight gains. More studies are needed in both children and adults to establish whether poorly controlled asthma leads to a more sedentary lifestyle and increasing obesity, whether obesity decreases asthma control, or both.

Several chronic health problems impact educational attainment and cognitive function.26 Determining whether asthma adversely affects cognitive function and educational attainment is complex and, not unexpectedly, the conclusions from different studies vary.2730 One reason for these differences is that most studies have not adjusted for other factors that impact on educational attainment and cognitive function, such as socioeconomic status, age/years in school, family composition, ethnicity, sex, skill level at school entry (“readiness”), and absenteeism. Moreover, virtually none of the studies included a thorough assessment of the level of asthma control in the patients studied. However, one prospective study, which did adjust for other potentially important factors, found that entering school with a diagnosis of asthma was a significant predictor of low achievement in reading at 12-month follow-up, independent of high absenteeism.31 This suggests an increased risk of academic problems among children with asthma compared with healthy children, but the study did not allow any conclusions about the influence of asthma control because that was not measured.

The findings in those studies that included some markers of asthma control were more consistent than in studies without any assessment of asthma control. After adjustment for demographic factors, children with poorly controlled asthma were twice as likely to have a reported learning disability compared with those with good asthma control.32 Also, children with asthma with parents who also have chronic disease have more poorly controlled asthma and miss more school than children with asthma who have healthy parents.33 Another study reported that nighttime awakenings in children with asthma (a marker of poor control) affected school performance.34 In addition, a study in adults found that psychometric tests assessing focused attention, mental flexibility, concentration, and attention were negatively affected in patients with untreated asthma compared with healthy control subjects.35 Circadian peak expired flow variation was the only independent factor significantly associated with impaired cognitive performance. Asthma treatment reduced circadian peak expired flow and improved FEV1 and after 6 weeks of therapy, the daytime cognitive performance was improved to levels comparable to those of the healthy control subjects. In addition, poor asthma control is associated with increased school absenteeism,36,37 and a program in schools to provide ICSs to children with asthma improved asthma control and reduced absenteeism, but only among children not exposed to secondhand smoke.38

In conclusion, uncontrolled asthma is associated with lower cognitive function and educational attainment. Improved asthma control using ICSs improved cognitive function and reduced school absenteeism. More studies are needed to evaluate the benefits of good asthma control on educational attainment.

There is evidence that asthma can influence mental health and vice versa.39,40 Families with specific emotional characteristics may be at an increased risk for poorer asthma outcomes. Moreover, in pediatric asthma both the psychologic characteristics of the affected children and their caregivers appear to contribute to the course of the condition. Unfortunately, the studies assessing these issues have not been designed to assess cause-effect relationships between the level of asthma control and behavioral and emotional characteristics.4144 However, some studies have suggested that uncontrolled asthma in a child is associated with greater parental anxiety and poorer quality of life for the parents,44,45 and others have suggested that stress is a risk factor for the onset of asthma,41 as well as for asthma exacerbations.42

Several studies have found that patients with asthma are at greater risk for depression compared with the general population.4648 In one study, the presence of anxiety or depressive disorders was 16.3% in the children with asthma and 8.6% in a control population.49 It was not possible to establish whether asthma led to the anxiety or depression or vice versa, or whether there was interplay between the two processes. In another study that included 1,480 twins, a diagnosis of asthma at ages 8 to 9 years of age was associated with attention deficit hyperactivity disorder 5 years later when the children were 13 to 14 years old.50 Children with asthma initially had a nearly twofold increase in the risk of having one or more symptoms of attention deficit hyperactivity disorder. The investigators found this association was independent of medication use. Because the study involved twins, modeling of the data was possible and indicated that 68% of the phenotype correlation could be attributed to genetic influences.

The impact of asthma control on the occurrence of depression has only been sparsely studied. However, some studies suggest that the level of control may be important. Patients with asthma with a history of depressive symptoms were found to have a significantly worse functional status than those without symptoms of depression.41 Furthermore, in the Childhood Asthma Management Program (CAMP) study,51 the occurrence of depressive symptoms and anxiety disorders was significantly less frequent in well-controlled patients with asthma (the ICS group), than in patients who were in the less well-controlled treatment groups. Findings in the Steroid Treatment as Regular Therapy (START) study52 corroborated this observation, in that patients treated with the ICS, budesonide, had better asthma control and significantly less depression, with trends for improvements in anxiety and behavioral disturbances, but did have significantly more oral candidiasis (Fig 2).

Figure Jump LinkFigure 2. Effect of treatment with the ICS budesonide, compared with non-ICS treatment on asthma control, oral candidiasis, anxiety, insomnia, depression, and behavioral disturbances in the Steroid Treatment as Regular Therapy (START) study (mean and 95% CI). ICS treatment significantly improved asthma control and depression and significantly increased the risk of oral candidiasis. ICS = inhaled corticosteroid; TTY = thousand treatment y.Grahic Jump Location

The most obvious relationship between asthma and mental health is the likelihood that the limitations to a normal lifestyle imposed by asthma affect the mental health of the patient. However, there are other associative data to suggest that this interaction may be more than simply the existence of an illness, or side effects from medications, which leads to anxiety or depression. First, there is evidence that prenatal anxiety in the mother is a risk factor for the eventual development of asthma.39 Second, the development of anxiety has been linked to a subsequent asthma exacerbation.42 Finally, low social economic status is associated with a shift toward a T helper cells type 2 profile which may enhance the expression of asthma.53 These observations suggest a more complex and bidirectional interaction between asthma and anxiety, and a model in which asthma may influence anxiety and anxiety influence asthma.

To test the hypothesis that chronic stress enhances the intensity of allergic inflammation in asthma, a study used final examinations in college as a cause of chronic stress to evaluate the influence on airway eosinophilia after an inhaled allergen challenge.54 The subjects recruited were studied on two separate occasions, in mid-semester, which was designated as a period of low stress, and then immediately after their final examination period, a period of high stress. The study demonstrated an expected increase in stress and anxiety with the final examination period when compared with mid-semester. In addition, there was a significant increase in sputum eosinophils after allergen challenge in the immediate postexamination period compared with mid-semester. Stress by itself did not change baseline sputum perimeters, but rather stress appeared to have primed the subjects such that when a second signal occurred, in this case an inhaled allergen, allergic inflammation was greater.

By using functional MRI (fMRI), it is possible to identify neurocircuits of the brain which have undergone activation in response to events that occur in the lung. To evaluate this, patients with asthma underwent three separate inhalation challenges, with saline, methacholine, and allergen.55 fMRI images were collected prior to the challenge and again at 4 h, a time prior to the onset of a late-phase reaction to inhaled allergen. In addition, sputum samples were collected 24 h postchallenge. Compared with the fMRI signal associated with methacholine, allergen provocation activated specific brain circuits at 4 h that was strongly correlated with the sputum eosinophil response. In addition, there was an inverse correlation with the fall in FEV1 in the late-phase response. These observations suggest that the airway inflammatory response is associated with an activation of specific areas of the brain, the anterior cingulate cortex and insula. Furthermore, given the timing of the fMRI signal, it is possible that this brain signal precedes and may determine the degree of airway inflammation that develops. What was not ascertained from these studies were the signals from the lung to the brain that activate these central circuits, and whether the activated circuits upregulate or downregulate the inflammatory response.

In conclusion, uncontrolled asthma is associated with an increased risk of developing stress, anxiety disorders, and depression. Improved asthma control during treatment with ICS may reduce the risks of depression and possibly stress and anxiety, although this is not yet well established.

Asthma exacerbations are common events which pose the greatest risk for patients with asthma incur the greatest asthma related treatment costs for the health-care system and for society in general.56 Severe asthma exacerbations are very often preceded by an upper respiratory tract infection (usually with human rhinovirus [HRV]),57,58 or by environmental allergen exposure in atopic individuals.59 However, despite the fact that all children, including those with asthma, are infected with one or more strains of HRV each year, not all infections are associated with severe exacerbations. This has led to the speculation that (1) HRV (or other respiratory viruses) acts as a cofactor in initiating acute severe events, but other conditions need to exist for this to happen, and (2) respiratory viruses and environmental allergens interact to precipitate asthma exacerbations to an extent that neither alone can achieve. This is supported by epidemiologic evidence which has indicated that the risks of being hospitalized with severe asthma exacerbations are increased by allergen sensitization alone (relative risk, 2.3; 95% CI, 1.0-5.4) and further increased by the combination of sensitization, high exposure to one or more allergens, and viral detection (relative risk, 8.4; 95% CI, 2.1-32.8).60

Viral-induced asthma exacerbations have a seasonal variability, as do upper respiratory tract infections (URTIs), being much more frequent in the fall and winter months.58 Indeed, hospital admissions for acute, severe asthma in childhood in Canada always peak during week 38 each year, which is 1 to 2 weeks after return to school after summer vacation. This has been ascribed to the “sharing” of upper respiratory viruses in the classroom.

The treatment of asthma with ICSs does not increase the risk of viral-induced asthma exacerbations; indeed, the overwhelming evidence is that regular ICS use reduces the overall risk of severe asthma exacerbations.52,61 While severe asthma exacerbations are usually relatively transient events, with full symptomatic recovery by the patient, they may be associated with a decline in lung function, which does not fully recover after the exacerbation has been treated and is resolved.62 Regular treatment with ICS diminishes this accelerated decline in lung function.62

Asthma has been associated with an increase in the risk of invasive pneumococcal infections.63 This was particularly obvious in patients with severe, uncontrolled asthma (patients with severe asthma exacerbations or who were requiring frequent rescue inhaled β2-agonist use); however, even in patients with better asthma control, the risk was higher than in patients who did not have asthma. The explanation for this increased risk is, as yet, not known, but the fact that the risks are higher with uncontrolled asthma suggests that persisting airway inflammation may be an aggravating factor. In addition, pneumococcal pneumonia is more frequent in asthmatic patients.64 Interestingly, this is also true for atopic patients and those with chronic obstructive lung disease (COPD).65 The OR is particularly increased in adult patients with asthma (OR, 6.7) when compared with matched control subjects. Once again, the mechanisms for this increase are not known, nor have the effects of ICS treatment on the increase in pneumococcal pneumonia been studied, but the overall effect of ICSs on pneumonia risk is known.

Oral corticosteroids are immunosuppressive and have been associated with increased risk of systemic and local infections. Thus, concern has existed that ICSs could potentially increase risks of viral respiratory infections, bacterial pneumonia, reactivation of pulmonary TB, or atypical infections (aspergillosis, pneumocystis, etc). This concern has been enhanced by data indicating that the ICS fluticasone propionate increases the risks of pneumonia in patients with COPD.66 A meta-analysis of studies of ICS alone or ICS plus long-acting β agonist (LABA) combinations in COPD indicates that the risk ratio is 1.7.67 A recent study has evaluated whether an increase in pneumonia risk exists in patients with asthma treated with the ICS budesonide.68 This study evaluated the reports of pneumonia as an adverse event (AE) or a serious adverse event (SAE) in 86 placebo-controlled and non-placebo-controlled studies which evaluated the efficacy of inhaled budesonide in asthma. In patients treated with placebo, an increased risk of pneumonia AE was identified in children aged < 12 years and adults > 60 years. These are the age ranges where the prevalence of pneumonia is highest in the general population. The study also identified a significant reduction in pneumonia reported as an AE in patients treated with inhaled budesonide, and no significant increase in pneumonia as a SAE in budesonide-treated patients (Fig 3). The reduction of pneumonia AE likely reflects incorrect allocation of respiratory events, which are known to be improved by ICSs, as pneumonia AEs. These would include segmental atelectasis due to mucous impaction (more often seen in children with poorly controlled asthma), increased cough and mucous production, or mild asthma exacerbations. The lack of an association between the use of budesonide in asthma and increased risks of pneumonia are supported by the fact that there was no dose response found when higher inhaled doses were compared with low doses, nor was an association seen in the smaller number of studies which used fluticasone propionate as a comparator in asthma. Also, there was no increased pneumonia with ICS treatment in patients with asthma with uncontrolled asthma at the baseline visit. Thus, in contrast to patients with COPD, ICS does not increase pneumonia risk in patients with asthma.

Figure Jump LinkFigure 3. A, Kaplan-Meier survival curves describing time to first pneumonia adverse event in patients treated with the ICS budesonide compared with placebo over 1 year. There was a significant reduction in pneumonia adverse events in the budesonide-treated group. B, Kaplan-Meier survival curves describing time to first pneumonia severe adverse event in patients treated with ICS compared with placebo over 1 year. There were no significant differences between the groups. See Figure 2 legend for expansion of abbreviations. (Reproduced with permission of the American Thoracic Society from O’Byrne et al.68)Grahic Jump Location

Reactivation of pulmonary TB is an identified complication of oral corticosteroid use. A recent case-controlled study has suggested that high doses of ICS may slightly increase risk of reactivation of TB in elderly patients with airflow obstruction.69 However, the START trial randomized 3,630 patients with newly diagnosed asthma (including many from countries where TB is endemic) to budesonide and 3,591 patients to placebo for 3 years, on top of their regular asthma treatment. In this study, six patients (0.17%) on budesonide and 10 patients (0.28%) on placebo reported TB. There are also single case reports of invasive aspergillosis70 and Pneumocystis carinii71 infection in immune-competent patients taking ICS.

In conclusion, asthma is associated with increased risk of invasive pneumococcal disease and pneumonia, and this risk appears to be greater when asthma is uncontrolled. Improved asthma control with ICSs reduces risk of severe asthma exacerbations (many caused by viral upper respiratory tract infections), but ICSs do not increase the risks of pneumonia although higher doses may increase the risks of reactivation of TB in adult patients with asthma.

Asthma is the most common potentially serious medical problem to complicate pregnancy.72 Pregnancy is a prototypical circumstance where one must consider both the risk of medications and the risk of the uncontrolled illness. Many women seem to believe that the risk of the medications is the greater risk—concerns about ICS safety73 and reduction of these medications during pregnancy74 are well documented, sometimes with grave fetal consequences.75 The available data strongly suggest that the much greater risk is from the uncontrolled asthma.

The most extreme adverse infant outcome is a perinatal death. A meta-analysis of 10 relevant studies76 showed a significant increased risk of perinatal mortality in the pregnancies of women with asthma compared with women who did not have asthma (OR, 1.25; 95% CI, 1.05-1.50). However, while the largest positive study reported a 40% unadjusted increased risk, the relationship became insignificant after adjusting for prematurity or smoking and abruption.77

Although the literature is somewhat conflicting, the available data suggests that maternal asthma increases the risk of preterm birth and low birth weight by 40% to 50%.76 A recent large administrative database study77 suggests that maternal asthma may significantly increase the risk of any major malformation by 34% and some specific malformations by 50% to 80%. Although confounding and common pathogenetic factors could contribute to some of these associations, the most modifiable mechanisms responsible for the increased risks would be poor asthma control and asthma medications.

Several types of observations suggest that poor asthma control is associated with an increased risk of adverse perinatal outcomes. Maternal mortality, fetal mortality, or both have been associated with severe asthma exacerbations during pregnancy.78,79 Although not possible to prove, it seems likely that these fatal outcomes would not have occurred in the absence of the asthma exacerbation. Several parameters of poor asthma control (increased symptoms, reduced FEV1, and exacerbations) have been associated with low birth weight, preterm birth, and/or size that is small for gestational age (SGA). Increased frequency80 and severity80 of symptoms have been associated with small size for gestational age and preterm birth, respectively. The large Maternal Fetal Medicine Unit study81 showed a relationship between reduced FEV1 and an increased incidence of both preterm-birth and low-birth-weight infants. A meta-analysis of three studies with adequate data82 demonstrated a relationship between maternal asthma exacerbations and infant low birth weight (Fig 4). Few data exist regarding the relationship of asthma control to congenital malformations, but one study did demonstrate a significant 48% increased risk of any congenital malformation in women with asthma who experienced an asthma exacerbation in the first trimester of pregnancy compared with women with asthma who did not suffer an exacerbation.83

Figure Jump LinkFigure 4. The relationship of asthma exacerbations during pregnancy to infant low birth weight. (Reproduced with permission of the BMJ Publishing Group from Murphy et al.82)Grahic Jump Location

Although all of these data suggest that improved asthma control would improve fetal outcomes, such observational data cannot prove such a cause-and-effect relationship. However, the randomized controlled trials needed to prove causal relationships between improved asthma control and improved perinatal outcomes (in which some women would need to be randomized to the poor control group) would be unethical.

Regarding the risks of asthma medications, substantial reassuring data exist for gestational use of short-acting β agonists (SABAs) and ICSs. ICS use was not associated with a significant increased risk of perinatal mortality in one large database study.84 Large prospective cohort studies have reported reassuring data regarding a lack of relationship of gestational exposure to SABAs or ICSs to prematurity or reduced fetal growth.85,86 Several large studies support the lack of association of ICS use with total or specific malformations.8789 One study90 has suggested a relationship between high-dose ICSs and total malformations, but confounding by severity is a possible explanation, based on the relationships between exacerbations and congenital malformations demonstrated by the same group.83 Bronchodilators have been associated with some specific malformations,87,91 but confounding by severity could explain these associations as well.

In contrast, oral corticosteroid use was associated with an increased risk of preterm birth81,85 and low-birth-weight infants85 in exposed women. An increased risk of orofacial clefts was reported in a meta-analysis of case-control studies,92 but this increased risk was not confirmed in a recent large cohort study.89 Since these risks would be less than the potential risks of a severe asthma exacerbation, which include maternal or fetal mortality, oral corticosteroids are recommended when indicated for the management of severe asthma during pregnancy.93

There are limited (but reassuring) data for use of leukotriene receptor antagonists during pregnancy.94,95 Although there are no substantial data regarding the gestational safety of long-acting β agonists (LABAs), their effectiveness in nonpregnant patients, inhaled route, and chemical similarities to SABAs have supported their recommended use during pregnancy when indicated.93,96 The reviewed data above support the conclusions of the most recent US consensus guidelines regarding the management of asthma during pregnancy93 indicating that the risks of uncontrolled asthma are substantially greater than the risks of recommended asthma medications.

In conclusion, poor asthma control increases risks of poor maternal and fetal outcomes. Guidelines for step therapy to achieve and maintain asthma control93,96 (Table 1) optimize maternal and fetal health in the pregnancies of women with asthma. Although randomized controlled trials cannot be done to answer the remaining questions, further well-designed large observational studies should help to confirm optimal benefit-risk considerations in the management of asthma during pregnancy.

Table Graphic Jump Location
Table 1 —Recommended Steps of Asthma Therapy During Pregnancy
a 

Budesonide is the preferred ICS for use during pregnancy, based on the availability of more reassuring data. However, there are no data to suggest that other ICSs are unsafe, and other ICSs may be continued in patients well controlled by them prior to pregnancy. ICS = inhaled corticosteroid; LABA = long-acting β agonist.

Despite the availability of effective and safe medications, many asthmatic patients remain uncontrolled.97,98 This is, in part, due to the lack of appropriate prescribing by the managing physician, and/or the lack of adherence to the prescribed medications.99 There are several reasons why patients do not adhere to prescribed treatment regimes, one of which is the fear of long-term side effects from the regular use of ICSs. This is, in part, a result of the well-known side effects and complications from the regular use of oral corticosteroids. These include obesity, stunted growth in children, metabolic complications, osteoporosis, immunosuppression, and the associated risks of infection, and cataracts. Many studies have evaluated the risks of ICS treatment on these side effects in patients with asthma, and have demonstrated no risks at the ICS doses used by almost all patients.68,100,101

Poorly controlled asthma adversely affects children’s cardiovascular fitness and ability to perform physically. Long-term improvement of the asthma control negates this impact, so that children with well-controlled asthma can perform physically at the same level as their peers. Children with newly diagnosed, uncontrolled asthma have a higher percentage of body fat and frequency of obesity than their healthy age-matched and sex-matched peers or children with controlled asthma. The annual weight gain before asthma is diagnosed is higher than in healthy children who do not have asthma. The annual weight gain in children with well-controlled asthma seems similar to the weight gain in healthy children. Poorly controlled asthma in children is also associated with reported learning disability and school performance. Additionally, in adults, focused attention, mental flexibility, concentration, and attention are negatively affected by poorly controlled asthma. In addition, depressive symptoms and anxiety disorders were significantly less frequent in children with well-controlled asthma.

Poorly controlled asthma increases the risks of pneumococcal pulmonary infections and severe asthma exacerbations following URTIs. ICS use to improve asthma control does not increase the risks of viral URTIs or pneumonia. High-dose ICS may slightly increase the risk of pulmonary TB in elderly patients with airflow obstruction. The risks of poorly controlled asthma during pregnancy are substantially greater than the risks of recommended asthma medications. Good asthma control improves maternal and fetal health during pregnancy in women with asthma.

This review presents evidence that uncontrolled asthma poses a greater risk for patients than the side effects of the medications used for its treatment. Improved understanding by patients that (1) the risks of poorly controlled asthma greatly outweigh the risks of adverse effects (particularly of ICS) and (2) the perceptions that these risks of uncontrolled asthma will be increased by ICS treatment are incorrect may help adherence with a significant advantage in overall health quality.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr O’Byrne has been on advisory boards for Almirall SA, AstraZeneca, GlaxoSmithKline plc, Merck & Co, and Takeda Pharmaceuticals International GmbH; has received lecture fees from Chiesi Farmaceutici SpA; and has received grants-in aid for research studies from Amgen Inc, Asmacure Ltée, AstraZeneca, and Genentech Inc. Dr Pedersen has participated in consultancy activities for AstraZeneca, GlaxoSmithKline plc, Neolab, and Takeda Pharmaceuticals International GmbH; and has spoken at meetings sponsored by GlaxoSmithKline plc and Takeda Pharmaceuticals International GmbH. Dr Schatz receives research grant support for investigator-initiated studies from Aerocrine, Genentech Inc, GlaxoSmithKline plc, and Merck & Co, and is a research consultant for Amgen Inc and GlaxoSmithKline plc. Drs Thoren, Ekholm, and Carlsson are employees of AstraZeneca. Dr Busse has provided advisory board services to Merck & Co; consultancy services to Amgen Inc, Novartis AG, GlaxoSmithKline plc, MedImmune LLC, and Genentech Inc; and received National Institutes of Health grant support from the National Institute of Allergy and Infectious Diseases and the National Heart, Lung, and Blood Institute.

AE

adverse event

fMRI

functional MRI

HRV

human rhinovirus

ICS

inhaled corticosteroid

LABA

long-acting β agonist

SABA

short-acting β agonist

SAE

serious adverse event

URTI

upper respiratory tract infection

National Asthma Education and Prevention ProgramNational Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): guidelines for the diagnosis and management of asthma-summary report 2007. [published correction appears inJ Allergy Clin Immunol. 2008;121(6):1330]. J Allergy Clin Immunol. 2007;120(suppl 5):S94-S138. [CrossRef] [PubMed]
 
Bateman ED, Hurd SS, Barnes PJ, et al. Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J. 2008;31(1):143-178. [CrossRef] [PubMed]
 
Reddel HK, Taylor DR, Bateman ED, et al;; American Thoracic Society/European Respiratory Society Task Force on Asthma Control and Exacerbations American Thoracic Society/European Respiratory Society Task Force on Asthma Control and Exacerbations. An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med. 2009;180(1):59-99. [CrossRef] [PubMed]
 
Bateman ED, Reddel HK, Eriksson G, et al. Overall asthma control: the relationship between current control and future risk. J Allergy Clin Immunol. 2010;125(3):600-608. [CrossRef] [PubMed]
 
Surgeon General’s report on physical activity and health. From the Centers for Disease Control and Prevention. JAMA. 1996;276(7):522. [CrossRef] [PubMed]
 
Strong WB, Malina RM, Blimkie CJ, et al. Evidence based physical activity for school-age youth. J Pediatr. 2005;146(6):732-737. [CrossRef] [PubMed]
 
Andersen LB, Sardinha LB, Froberg K, Riddoch CJ, Page AS, Anderssen SA. Fitness, fatness and clustering of cardiovascular risk factors in children from Denmark, Estonia and Portugal: the European Youth Heart Study. Int J Pediatr Obes. 2008;3(suppl 1):58-66. [CrossRef] [PubMed]
 
Nystad W. The physical activity level in children with asthma based on a survey among 7-16 year old school children. Scand J Med Sci Sports. 1997;7(6):331-335. [CrossRef] [PubMed]
 
van Gent R, van der Ent CK, van Essen-Zandvliet LE, et al. No differences in physical activity in (un)diagnosed asthma and healthy controls. Pediatr Pulmonol. 2007;42(11):1018-1023. [CrossRef] [PubMed]
 
Chiang LC, Huang JL, Fu LS. Physical activity and physical self-concept: comparison between children with and without asthma. J Adv Nurs. 2006;54(6):653-662. [CrossRef] [PubMed]
 
Lang DM, Butz AM, Duggan AK, Serwint JR. Physical activity in urban school-aged children with asthma. Pediatrics. 2004;113(4):e341-e346. [CrossRef] [PubMed]
 
Berntsen S, Carlsen KC, Anderssen SA, et al. Norwegian adolescents with asthma are physical active and fit. Allergy. 2009;64(3):421-426. [CrossRef] [PubMed]
 
Vahlkvist S, Inman MD, Pedersen S. Effect of asthma treatment on fitness, daily activity and body composition in children with asthma. Allergy. 2010;65(11):1464-1471. [CrossRef] [PubMed]
 
Vahlkvist S, Pedersen S. Fitness, daily activity and body composition in children with newly diagnosed, untreated asthma. Allergy. 2009;64(11):1649-1655. [CrossRef] [PubMed]
 
Brasholt M, Baty F, Bisgaard H. Physical activity in young children is reduced with increasing bronchial responsiveness. J Allergy Clin Immunol. 2010;125(5):1007-1012. [CrossRef] [PubMed]
 
Dencker M, Andersen LB. Health-related aspects of objectively measured daily physical activity in children. Clin Physiol Funct Imaging. 2008;28(3):133-144. [CrossRef] [PubMed]
 
Janz KF, Burns TL, Levy SM; Iowa Bone Development Study Iowa Bone Development Study. Tracking of activity and sedentary behaviors in childhood: the Iowa Bone Development Study. Am J Prev Med. 2005;29(3):171-178. [CrossRef] [PubMed]
 
Moore LL, Gao D, Bradlee ML, et al. Does early physical activity predict body fat change throughout childhood? Prev Med. 2003;37(1):10-17. [CrossRef] [PubMed]
 
Stevens J, Murray DM, Baggett CD, et al. Objectively assessed associations between physical activity and body composition in middle-school girls: the Trial of Activity for Adolescent Girls. Am J Epidemiol. 2007;166(11):1298-1305. [CrossRef] [PubMed]
 
Gold DR, Damokosh AI, Dockery DW, Berkey CS. Body-mass index as a predictor of incident asthma in a prospective cohort of children. Pediatr Pulmonol. 2003;36(6):514-521. [CrossRef] [PubMed]
 
Castro-Rodríguez JA, Holberg CJ, Morgan WJ, Wright AL, Martinez FD. Increased incidence of asthmalike symptoms in girls who become overweight or obese during the school years. Am J Respir Crit Care Med. 2001;163(6):1344-1349. [PubMed]
 
Matricardi PM, Grüber C, Wahn U, Lau S. The asthma-obesity link in childhood: open questions, complex evidence, a few answers only. Clin Exp Allergy. 2007;37(4):476-484. [CrossRef] [PubMed]
 
Pianosi PT, Davis HS. Determinants of physical fitness in children with asthma. Pediatrics. 2004;113(3 pt 1):e225-e229. [CrossRef] [PubMed]
 
van Veen IH, Ten Brinke A, Sterk PJ, Rabe KF, Bel EH. Airway inflammation in obese and nonobese patients with difficult-to-treat asthma. Allergy. 2008;63(5):570-574. [CrossRef] [PubMed]
 
Santamaria F, Montella S, De Stefano S, et al. Asthma, atopy, and airway inflammation in obese children. J Allergy Clin Immunol. 2007;120(4):965-967. [CrossRef] [PubMed]
 
Thies KM. Identifying the educational implications of chronic illness in school children. J Sch Health. 1999;69(10):392-397. [CrossRef] [PubMed]
 
Gutstadt LB, Gillette JW, Mrazek DA, Fukuhara JT, LaBrecque JF, Strunk RC. Determinants of school performance in children with chronic asthma. Am J Dis Child. 1989;143(:471-475. [PubMed]
 
Celano MP, Geller RJ. Learning, school performance, and children with asthma: how much at risk? J Learn Disabil. 1993;26(1):23-32. [CrossRef] [PubMed]
 
Moonie S, Sterling DA, Figgs LW, Castro M. The relationship between school absence, academic performance, and asthma status. J Sch Health. 2008;78(3):140-148. [CrossRef] [PubMed]
 
Liberty KA, Pattemore P, Reid J, Tarren-Sweeney M. Beginning school with asthma independently predicts low achievement in a prospective cohort of children. Chest. 2010;138(6):1349-1355. [CrossRef] [PubMed]
 
Fowler MG, Davenport MG, Garg R. School functioning of US children with asthma. Pediatrics. 1992;90(6):939-944. [PubMed]
 
Diette GB, Markson L, Skinner EA, Nguyen TT, Algatt-Bergstrom P, Wu AW. Nocturnal asthma in children affects school attendance, school performance, and parents’ work attendance. Arch Pediatr Adolesc Med. 2000;154(9):923-928. [PubMed]
 
Lipstein EA, Perrin JM, Kuhlthau KA. School absenteeism, health status, and health care utilization among children with asthma: associations with parental chronic disease. Pediatrics. 2009;123(1):e60-e66. [CrossRef] [PubMed]
 
Weersink EJ, van Zomeren EH, Koëter GH, Postma DS. Treatment of nocturnal airway obstruction improves daytime cognitive performance in asthmatics. Am J Respir Crit Care Med. 1997;156(4 Pt 1):1144-1150. [PubMed]
 
Strine TW, Mokdad AH, Balluz LS, Berry JT, Gonzalez O. Impact of depression and anxiety on quality of life, health behaviors, and asthma control among adults in the United States with asthma, 2006. J Asthma. 2008;45(2):123-133. [CrossRef] [PubMed]
 
Schmier JK, Manjunath R, Halpern MT, Jones ML, Thompson K, Diette GB. The impact of inadequately controlled asthma in urban children on quality of life and productivity. Ann Allergy Asthma Immunol. 2007;98(3):245-251. [CrossRef] [PubMed]
 
Dean BB, Calimlim BM, Kindermann SL, Khandker RK, Tinkelman D. The impact of uncontrolled asthma on absenteeism and health-related quality of life. J Asthma. 2009;46(9):861-866. [CrossRef] [PubMed]
 
Halterman JS, Szilagyi PG, Yoos HL, et al. Benefits of a school-based asthma treatment program in the absence of secondhand smoke exposure: results of a randomized clinical trial. Arch Pediatr Adolesc Med. 2004;158(5):460-467. [CrossRef] [PubMed]
 
Wright RJ, Cohen S, Carey V, Weiss ST, Gold DR. Parental stress as a predictor of wheezing in infancy: a prospective birth-cohort study. Am J Respir Crit Care Med. 2002;165(3):358-365. [PubMed]
 
Isenberg SA, Lehrer PM, Hochron S. The effects of suggestion and emotional arousal on pulmonary function in asthma: a review and a hypothesis regarding vagal mediation. Psychosom Med. 1992;54(2):192-216. [PubMed]
 
Tibosch MM, Verhaak CM, Merkus PJ. Psychological characteristics associated with the onset and course of asthma in children and adolescents: a systematic review of longitudinal effects. Patient Educ Couns. 2011;82(1):11-19. [CrossRef] [PubMed]
 
Sandberg S, Järvenpää S, Penttinen A, Paton JY, McCann DC. Asthma exacerbations in children immediately following stressful life events: a Cox’s hierarchical regression. Thorax. 2004;59(12):1046-1051. [CrossRef] [PubMed]
 
Kaugars AS, Klinnert MD, Bender BG. Family influences on pediatric asthma. J Pediatr Psychol. 2004;29(7):475-491. [CrossRef] [PubMed]
 
Wood BL, Miller BD, Lim J, et al. Family relational factors in pediatric depression and asthma: pathways of effect. J Am Acad Child Adolesc Psychiatry. 2006;45(12):1494-1502. [CrossRef] [PubMed]
 
Szefler SJ, Baker JW, Uryniak T, Goldman M, Silkoff PE. Comparative study of budesonide inhalation suspension and montelukast in young children with mild persistent asthma. J Allergy Clin Immunol. 2007;120(5):1043-1050. [CrossRef] [PubMed]
 
Adams RJ, Wilson DH, Taylor AW, et al. Psychological factors and asthma quality of life: a population based study. Thorax. 2004;59(11):930-935. [CrossRef] [PubMed]
 
Scott KM, Von Korff M, Ormel J, et al. Mental disorders among adults with asthma: results from the World Mental Health Survey. Gen Hosp Psychiatry. 2007;29(2):123-133. [CrossRef] [PubMed]
 
Mancuso CA, Peterson MG, Charlson ME. Effects of depressive symptoms on health-related quality of life in asthma patients. J Gen Intern Med. 2000;15(5):301-310. [CrossRef] [PubMed]
 
Katon WJ, Richardson L, Lozano P, McCauley E. The relationship of asthma and anxiety disorders. Psychosom Med. 2004;66(3):349-355. [CrossRef] [PubMed]
 
Mogensen N, Larsson H, Lundholm C, Almqvist C. Association between childhood asthma and ADHD symptoms in adolescence—a prospective population-based twin study. Allergy. 2011;66(9):1224-1230. [CrossRef] [PubMed]
 
Long-term effects of budesonide or nedocromil in children with asthma. The Childhood Asthma Management Program Research Group. N Engl J Med. 2000;343(15):1054-1063. [CrossRef] [PubMed]
 
Pauwels RA, Pedersen S, Busse WW, et al;; START Investigators Group START Investigators Group. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet. 2003;361(9363):1071-1076. [CrossRef] [PubMed]
 
Chen E, Hanson MD, Paterson LQ, Griffin MJ, Walker HA, Miller GE. Socioeconomic status and inflammatory processes in childhood asthma: the role of psychological stress. J Allergy Clin Immunol. 2006;117(5):1014-1020. [CrossRef] [PubMed]
 
Liu LY, Coe CL, Swenson CA, Kelly EA, Kita H, Busse WW. School examinations enhance airway inflammation to antigen challenge. Am J Respir Crit Care Med. 2002;165(8):1062-1067. [PubMed]
 
Rosenkranz MA, Busse WW, Johnstone T, et al. Neural circuitry underlying the interaction between emotion and asthma symptom exacerbation. Proc Natl Acad Sci U S A. 2005;102(37):13319-13324. [CrossRef] [PubMed]
 
Barnett SB, Nurmagambetov TA. Costs of asthma in the United States: 2002-2007. J Allergy Clin Immunol. 2011;127(1):145-152. [CrossRef] [PubMed]
 
Johnston SL, Pattemore PK, Sanderson G, et al. Community study of role of viral infections in exacerbations of asthma in 9-11 year old children. BMJ. 1995;310(6989):1225-1229. [CrossRef] [PubMed]
 
Johnston NW, Johnston SL, Duncan JM, et al. The September epidemic of asthma exacerbations in children: a search for etiology. J Allergy Clin Immunol. 2005;115(1):132-138. [CrossRef] [PubMed]
 
Boulet LP, Cartier A, Thomson NC, Roberts RS, Dolovich J, Hargreave FE. Asthma and increases in nonallergic bronchial responsiveness from seasonal pollen exposure. J Allergy Clin Immunol. 1983;71(4):399-406. [CrossRef] [PubMed]
 
Green RM, Custovic A, Sanderson G, Hunter J, Johnston SL, Woodcock A. Synergism between allergens and viruses and risk of hospital admission with asthma: case-control study.. [published correction appears inBMJ. 2002;324(7346):1131]. BMJ. 2002;324(7340):763. [CrossRef] [PubMed]
 
O’Byrne PM, Barnes PJ, Rodriguez-Roisin R, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care Med. 2001;164(8 Pt 1):1392-1397. [PubMed]
 
O’Byrne PM, Pedersen S, Lamm CJ, Tan WC, Busse WW; START Investigators Group START Investigators Group. Severe exacerbations and decline in lung function in asthma.. [published correction appears inAm J Respir Crit Care Med. 2010;182(7):983-984]. Am J Respir Crit Care Med. 2009;179(1):19-24. [CrossRef] [PubMed]
 
Talbot TR, Hartert TV, Mitchel E, et al. Asthma as a risk factor for invasive pneumococcal disease. N Engl J Med. 2005;352(20):2082-2090. [CrossRef] [PubMed]
 
Schmidt M, Sun G, Stacey MA, Mori L, Mattoli S. Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma. J Immunol. 2003;171(1):380-389. [PubMed]
 
Saunders R, Siddiqui S, Kaur D, et al. Fibrocyte localization to the airway smooth muscle is a feature of asthma. J Allergy Clin Immunol. 2009;123(2):376-384. [CrossRef] [PubMed]
 
Ernst P, Gonzalez AV, Brassard P, Suissa S. Inhaled corticosteroid use in chronic obstructive pulmonary disease and the risk of hospitalization for pneumonia. Am J Respir Crit Care Med. 2007;176(2):162-166. [CrossRef] [PubMed]
 
Singh S, Amin AV, Loke YK. Long-term use of inhaled corticosteroids and the risk of pneumonia in chronic obstructive pulmonary disease: a meta-analysis. Arch Intern Med. 2009;169(3):219-229. [CrossRef] [PubMed]
 
O’Byrne PM, Pedersen S, Carlsson LG, et al. Risks of pneumonia in patients with asthma taking inhaled corticosteroids. Am J Respir Crit Care Med. 2011;183(5):589-595. [CrossRef] [PubMed]
 
Brassard P, Suissa S, Kezouh A, Ernst P. Inhaled corticosteroids and risk of tuberculosis in patients with respiratory diseases. Am J Respir Crit Care Med. 2011;183(5):675-678. [CrossRef] [PubMed]
 
Barouky R, Badet M, Denis MS, Soubirou JL, Philit F, Guerin C. Inhaled corticosteroids in chronic obstructive pulmonary disease and disseminated aspergillosis. Eur J Intern Med. 2003;14(6):380-382. [CrossRef] [PubMed]
 
Sy ML, Chin TW, Nussbaum E. Pneumocystis carinii pneumonia associated with inhaled corticosteroids in an immunocompetent child with asthma. J Pediatr. 1995;127(6):1000-1002.
 
Kwon HL, Triche EW, Belanger K, Bracken MB. The epidemiology of asthma during pregnancy: prevalence, diagnosis, and symptoms. Immunol Allergy Clin North Am. 2006;26(1):29-62. [CrossRef] [PubMed]
 
Chambers K. Asthma education and outcomes for women of childbearing age. Case Manager. 2003;14(6):58-61. [CrossRef] [PubMed]
 
Enriquez R, Wu P, Griffin MR, et al. Cessation of asthma medication in early pregnancy. Am J Obstet Gynecol. 2006;195(1):149-153. [CrossRef] [PubMed]
 
Sugai K, Ito M, Tateishi I, Funabiki T, Nishikawa M. Neonatal periventricular leukomalacia due to severe, poorly controlled asthma in the mother. Allergol Int. 2006;55(2):207-212. [CrossRef] [PubMed]
 
Murphy VE, Namazy JA, Powell H, et al. A meta-analysis of adverse perinatal outcomes in women with asthma. BJOG. 2011;118(11):1314-1323. [CrossRef] [PubMed]
 
Breton MC, Beauchesne MF, Lemière C, Rey E, Forget A, Blais L. Risk of perinatal mortality associated with asthma during pregnancy: a 2-stage sampling cohort study. Ann Allergy Asthma Immunol. 2010;105(3):211-217. [CrossRef] [PubMed]
 
Blais L, Kettani FZ, Elftouh N, Forget A. Effect of maternal asthma on the risk of specific congenital malformations: a population-based cohort study. Birth Defects Res A Clin Mol Teratol. 2010;88(4):216-222. [PubMed]
 
Gordon M, Niswander KR, Berendes H, Kantor AG. Fetal morbidity following potentially anoxigenic obstetric conditions. VII. Bronchial asthma. Am J Obstet Gynecol. 1970;106(3):421-429. [PubMed]
 
Gelber M, Sidi Y, Gassner S, et al. Uncontrollable life-threatening status asthmaticus—an indicator for termination of pregnancy by cesarean section. Respiration. 1984;46(3):320-322. [CrossRef] [PubMed]
 
Bracken MB, Triche EW, Belanger K, Saftlas A, Beckett WS, Leaderer BP. Asthma symptoms, severity, and drug therapy: a prospective study of effects on 2205 pregnancies. Obstet Gynecol. 2003;102(4):739-752. [CrossRef] [PubMed]
 
Murphy VE, Clifton VL, Gibson PG. Asthma exacerbations during pregnancy: incidence and association with adverse pregnancy outcomes. Thorax. 2006;61(2):169-176. [CrossRef] [PubMed]
 
Blais L, Forget A.. Asthma exacerbations during the first trimester of pregnancy and the risk of congenital malformations among asthmatic women. J Allergy Clin Immunol. 2008;121(6):1379-1384.
 
Breton MC, Beauchesne MF, Lemière C, Rey É, Forget A, Blais L. Risk of perinatal mortality associated with inhaled corticosteroid use for the treatment of asthma during pregnancy. J Allergy Clin Immunol. 2010;126(4):772-777.-, e2. [CrossRef] [PubMed]
 
Schatz M, Dombrowski MP, Wise R, et al;; Maternal-Fetal Medicine Units Network, The National Institute of Child Health and Development Maternal-Fetal Medicine Units Network, The National Institute of Child Health and Development; National Heart, Lung and Blood Institute National Heart, Lung and Blood Institute. The relationship of asthma medication use to perinatal outcomes. J Allergy Clin Immunol. 2004;113(6):1040-1045. [CrossRef] [PubMed]
 
Schatz M, Zeiger RS, Harden K, Hoffman CC, Chilingar L, Petitti D. The safety of asthma and allergy medications during pregnancy. J Allergy Clin Immunol. 1997;100(3):301-306. [CrossRef] [PubMed]
 
Källén B, Otterblad Olausson P. Use of anti-asthmatic drugs during pregnancy. 3. Congenital malformations in the infants. Eur J Clin Pharmacol. 2007;63(4):383-388. [CrossRef] [PubMed]
 
Blais L, Beauchesne MF, Rey E, Malo JL, Forget A. Use of inhaled corticosteroids during the first trimester of pregnancy and the risk of congenital malformations among women with asthma. Thorax. 2007;62(4):320-328. [CrossRef] [PubMed]
 
Hviid A, Mølgaard-Nielsen D. Corticosteroid use during pregnancy and risk of orofacial clefts. CMAJ. 2011;183(7):796-804. [PubMed]
 
Blais L, Beauchesne MF, Lemière C, Elftouh N. High doses of inhaled corticosteroids during the first trimester of pregnancy and congenital malformations. J Allergy Clin Immunol. 2009;124(6):1229-1234. [CrossRef] [PubMed]
 
Lin S, Munsie JP, Herdt-Losavio ML, et al;; National Birth Defects Prevention Study National Birth Defects Prevention Study. Maternal asthma medication use and the risk of gastroschisis. Am J Epidemiol. 2008;168(1):73-79. [CrossRef] [PubMed]
 
Park-Wyllie L, Mazzotta P, Pastuszak A, et al. Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies. Teratology. 2000;62(6):385-392. [CrossRef] [PubMed]
 
National Heart, Lung, and Blood InstituteNational Heart, Lung, and Blood Institute; National Asthma Education and Prevention Program Asthma and Pregnancy Working Group National Asthma Education and Prevention Program Asthma and Pregnancy Working Group. NAEPP expert panel report. Managing asthma during pregnancy: recommendations for pharmacologic treatment-2004 update. J Allergy Clin Immunol. 2005;115(1):34-46. [CrossRef] [PubMed]
 
Bakhireva LN, Jones KL, Schatz M, et al;; Organization of Teratology Information Specialists Collaborative Research Group Organization of Teratology Information Specialists Collaborative Research Group. Safety of leukotriene receptor antagonists in pregnancy. J Allergy Clin Immunol. 2007;119(3):618-625. [CrossRef] [PubMed]
 
Sarkar M, Koren G, Kalra S, et al. Montelukast use during pregnancy: a multicentre, prospective, comparative study of infant outcomes. Eur J Clin Pharmacol. 2009;65(12):1259-1264. [CrossRef] [PubMed]
 
Schatz M, Dombrowski MP. Clinical practice. Asthma in pregnancy. N Engl J Med. 2009;360(18):1862-1869. [CrossRef] [PubMed]
 
Rabe KF, Adachi M, Lai CK, et al. Worldwide severity and control of asthma in children and adults: the global asthma insights and reality surveys. J Allergy Clin Immunol. 2004;114(1):40-47. [CrossRef] [PubMed]
 
Chapman KR, Boulet LP, Rea RM, Franssen E. Suboptimal asthma control: prevalence, detection and consequences in general practice. Eur Respir J. 2008;31(2):320-325. [CrossRef] [PubMed]
 
Williams LK, Joseph CL, Peterson EL, et al. Patients with asthma who do not fill their inhaled corticosteroids: a study of primary nonadherence. J Allergy Clin Immunol. 2007;120(5):1153-1159. [CrossRef] [PubMed]
 
Agertoft L, Pedersen S. Effect of long-term treatment with inhaled budesonide on adult height in children with asthma. N Engl J Med. 2000;343(15):1064-1069. [CrossRef] [PubMed]
 
Kelly HW, Van Natta ML, Covar RA, Tonascia J, Green RP, Strunk RC; CAMP Research Group CAMP Research Group. Effect of long-term corticosteroid use on bone mineral density in children: a prospective longitudinal assessment in the childhood Asthma Management Program (CAMP) study. Pediatrics. 2008;122(1):e53-e61. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. A, B, Changes from baseline in time spent in (A) total daily activity and (B) vigorous daily activity in children with asthma and their age-matched and sex-matched healthy control subjects during 1 year of guideline-recommended treatment of the patients with asthma. Improvement of asthma control was associated with statistically significant improvements in daily physical activity compared with the control children. C, Before treatment, children with asthma were less fit than their healthy control subjects. D, But their fitness improved significantly more than the fitness of the healthy children when the asthma was treated. The greatest improvements in daily activity and fitness were seen in the children with the poorest asthma control at baseline and greatest improvements in control during treatment. V˙ O2max = maximum oxygen consumption. (Data derived from Vahlkvist and Pedersen14 and Brasholt et al.15)Grahic Jump Location
Figure Jump LinkFigure 2. Effect of treatment with the ICS budesonide, compared with non-ICS treatment on asthma control, oral candidiasis, anxiety, insomnia, depression, and behavioral disturbances in the Steroid Treatment as Regular Therapy (START) study (mean and 95% CI). ICS treatment significantly improved asthma control and depression and significantly increased the risk of oral candidiasis. ICS = inhaled corticosteroid; TTY = thousand treatment y.Grahic Jump Location
Figure Jump LinkFigure 3. A, Kaplan-Meier survival curves describing time to first pneumonia adverse event in patients treated with the ICS budesonide compared with placebo over 1 year. There was a significant reduction in pneumonia adverse events in the budesonide-treated group. B, Kaplan-Meier survival curves describing time to first pneumonia severe adverse event in patients treated with ICS compared with placebo over 1 year. There were no significant differences between the groups. See Figure 2 legend for expansion of abbreviations. (Reproduced with permission of the American Thoracic Society from O’Byrne et al.68)Grahic Jump Location
Figure Jump LinkFigure 4. The relationship of asthma exacerbations during pregnancy to infant low birth weight. (Reproduced with permission of the BMJ Publishing Group from Murphy et al.82)Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Recommended Steps of Asthma Therapy During Pregnancy
a 

Budesonide is the preferred ICS for use during pregnancy, based on the availability of more reassuring data. However, there are no data to suggest that other ICSs are unsafe, and other ICSs may be continued in patients well controlled by them prior to pregnancy. ICS = inhaled corticosteroid; LABA = long-acting β agonist.

References

National Asthma Education and Prevention ProgramNational Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): guidelines for the diagnosis and management of asthma-summary report 2007. [published correction appears inJ Allergy Clin Immunol. 2008;121(6):1330]. J Allergy Clin Immunol. 2007;120(suppl 5):S94-S138. [CrossRef] [PubMed]
 
Bateman ED, Hurd SS, Barnes PJ, et al. Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J. 2008;31(1):143-178. [CrossRef] [PubMed]
 
Reddel HK, Taylor DR, Bateman ED, et al;; American Thoracic Society/European Respiratory Society Task Force on Asthma Control and Exacerbations American Thoracic Society/European Respiratory Society Task Force on Asthma Control and Exacerbations. An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med. 2009;180(1):59-99. [CrossRef] [PubMed]
 
Bateman ED, Reddel HK, Eriksson G, et al. Overall asthma control: the relationship between current control and future risk. J Allergy Clin Immunol. 2010;125(3):600-608. [CrossRef] [PubMed]
 
Surgeon General’s report on physical activity and health. From the Centers for Disease Control and Prevention. JAMA. 1996;276(7):522. [CrossRef] [PubMed]
 
Strong WB, Malina RM, Blimkie CJ, et al. Evidence based physical activity for school-age youth. J Pediatr. 2005;146(6):732-737. [CrossRef] [PubMed]
 
Andersen LB, Sardinha LB, Froberg K, Riddoch CJ, Page AS, Anderssen SA. Fitness, fatness and clustering of cardiovascular risk factors in children from Denmark, Estonia and Portugal: the European Youth Heart Study. Int J Pediatr Obes. 2008;3(suppl 1):58-66. [CrossRef] [PubMed]
 
Nystad W. The physical activity level in children with asthma based on a survey among 7-16 year old school children. Scand J Med Sci Sports. 1997;7(6):331-335. [CrossRef] [PubMed]
 
van Gent R, van der Ent CK, van Essen-Zandvliet LE, et al. No differences in physical activity in (un)diagnosed asthma and healthy controls. Pediatr Pulmonol. 2007;42(11):1018-1023. [CrossRef] [PubMed]
 
Chiang LC, Huang JL, Fu LS. Physical activity and physical self-concept: comparison between children with and without asthma. J Adv Nurs. 2006;54(6):653-662. [CrossRef] [PubMed]
 
Lang DM, Butz AM, Duggan AK, Serwint JR. Physical activity in urban school-aged children with asthma. Pediatrics. 2004;113(4):e341-e346. [CrossRef] [PubMed]
 
Berntsen S, Carlsen KC, Anderssen SA, et al. Norwegian adolescents with asthma are physical active and fit. Allergy. 2009;64(3):421-426. [CrossRef] [PubMed]
 
Vahlkvist S, Inman MD, Pedersen S. Effect of asthma treatment on fitness, daily activity and body composition in children with asthma. Allergy. 2010;65(11):1464-1471. [CrossRef] [PubMed]
 
Vahlkvist S, Pedersen S. Fitness, daily activity and body composition in children with newly diagnosed, untreated asthma. Allergy. 2009;64(11):1649-1655. [CrossRef] [PubMed]
 
Brasholt M, Baty F, Bisgaard H. Physical activity in young children is reduced with increasing bronchial responsiveness. J Allergy Clin Immunol. 2010;125(5):1007-1012. [CrossRef] [PubMed]
 
Dencker M, Andersen LB. Health-related aspects of objectively measured daily physical activity in children. Clin Physiol Funct Imaging. 2008;28(3):133-144. [CrossRef] [PubMed]
 
Janz KF, Burns TL, Levy SM; Iowa Bone Development Study Iowa Bone Development Study. Tracking of activity and sedentary behaviors in childhood: the Iowa Bone Development Study. Am J Prev Med. 2005;29(3):171-178. [CrossRef] [PubMed]
 
Moore LL, Gao D, Bradlee ML, et al. Does early physical activity predict body fat change throughout childhood? Prev Med. 2003;37(1):10-17. [CrossRef] [PubMed]
 
Stevens J, Murray DM, Baggett CD, et al. Objectively assessed associations between physical activity and body composition in middle-school girls: the Trial of Activity for Adolescent Girls. Am J Epidemiol. 2007;166(11):1298-1305. [CrossRef] [PubMed]
 
Gold DR, Damokosh AI, Dockery DW, Berkey CS. Body-mass index as a predictor of incident asthma in a prospective cohort of children. Pediatr Pulmonol. 2003;36(6):514-521. [CrossRef] [PubMed]
 
Castro-Rodríguez JA, Holberg CJ, Morgan WJ, Wright AL, Martinez FD. Increased incidence of asthmalike symptoms in girls who become overweight or obese during the school years. Am J Respir Crit Care Med. 2001;163(6):1344-1349. [PubMed]
 
Matricardi PM, Grüber C, Wahn U, Lau S. The asthma-obesity link in childhood: open questions, complex evidence, a few answers only. Clin Exp Allergy. 2007;37(4):476-484. [CrossRef] [PubMed]
 
Pianosi PT, Davis HS. Determinants of physical fitness in children with asthma. Pediatrics. 2004;113(3 pt 1):e225-e229. [CrossRef] [PubMed]
 
van Veen IH, Ten Brinke A, Sterk PJ, Rabe KF, Bel EH. Airway inflammation in obese and nonobese patients with difficult-to-treat asthma. Allergy. 2008;63(5):570-574. [CrossRef] [PubMed]
 
Santamaria F, Montella S, De Stefano S, et al. Asthma, atopy, and airway inflammation in obese children. J Allergy Clin Immunol. 2007;120(4):965-967. [CrossRef] [PubMed]
 
Thies KM. Identifying the educational implications of chronic illness in school children. J Sch Health. 1999;69(10):392-397. [CrossRef] [PubMed]
 
Gutstadt LB, Gillette JW, Mrazek DA, Fukuhara JT, LaBrecque JF, Strunk RC. Determinants of school performance in children with chronic asthma. Am J Dis Child. 1989;143(:471-475. [PubMed]
 
Celano MP, Geller RJ. Learning, school performance, and children with asthma: how much at risk? J Learn Disabil. 1993;26(1):23-32. [CrossRef] [PubMed]
 
Moonie S, Sterling DA, Figgs LW, Castro M. The relationship between school absence, academic performance, and asthma status. J Sch Health. 2008;78(3):140-148. [CrossRef] [PubMed]
 
Liberty KA, Pattemore P, Reid J, Tarren-Sweeney M. Beginning school with asthma independently predicts low achievement in a prospective cohort of children. Chest. 2010;138(6):1349-1355. [CrossRef] [PubMed]
 
Fowler MG, Davenport MG, Garg R. School functioning of US children with asthma. Pediatrics. 1992;90(6):939-944. [PubMed]
 
Diette GB, Markson L, Skinner EA, Nguyen TT, Algatt-Bergstrom P, Wu AW. Nocturnal asthma in children affects school attendance, school performance, and parents’ work attendance. Arch Pediatr Adolesc Med. 2000;154(9):923-928. [PubMed]
 
Lipstein EA, Perrin JM, Kuhlthau KA. School absenteeism, health status, and health care utilization among children with asthma: associations with parental chronic disease. Pediatrics. 2009;123(1):e60-e66. [CrossRef] [PubMed]
 
Weersink EJ, van Zomeren EH, Koëter GH, Postma DS. Treatment of nocturnal airway obstruction improves daytime cognitive performance in asthmatics. Am J Respir Crit Care Med. 1997;156(4 Pt 1):1144-1150. [PubMed]
 
Strine TW, Mokdad AH, Balluz LS, Berry JT, Gonzalez O. Impact of depression and anxiety on quality of life, health behaviors, and asthma control among adults in the United States with asthma, 2006. J Asthma. 2008;45(2):123-133. [CrossRef] [PubMed]
 
Schmier JK, Manjunath R, Halpern MT, Jones ML, Thompson K, Diette GB. The impact of inadequately controlled asthma in urban children on quality of life and productivity. Ann Allergy Asthma Immunol. 2007;98(3):245-251. [CrossRef] [PubMed]
 
Dean BB, Calimlim BM, Kindermann SL, Khandker RK, Tinkelman D. The impact of uncontrolled asthma on absenteeism and health-related quality of life. J Asthma. 2009;46(9):861-866. [CrossRef] [PubMed]
 
Halterman JS, Szilagyi PG, Yoos HL, et al. Benefits of a school-based asthma treatment program in the absence of secondhand smoke exposure: results of a randomized clinical trial. Arch Pediatr Adolesc Med. 2004;158(5):460-467. [CrossRef] [PubMed]
 
Wright RJ, Cohen S, Carey V, Weiss ST, Gold DR. Parental stress as a predictor of wheezing in infancy: a prospective birth-cohort study. Am J Respir Crit Care Med. 2002;165(3):358-365. [PubMed]
 
Isenberg SA, Lehrer PM, Hochron S. The effects of suggestion and emotional arousal on pulmonary function in asthma: a review and a hypothesis regarding vagal mediation. Psychosom Med. 1992;54(2):192-216. [PubMed]
 
Tibosch MM, Verhaak CM, Merkus PJ. Psychological characteristics associated with the onset and course of asthma in children and adolescents: a systematic review of longitudinal effects. Patient Educ Couns. 2011;82(1):11-19. [CrossRef] [PubMed]
 
Sandberg S, Järvenpää S, Penttinen A, Paton JY, McCann DC. Asthma exacerbations in children immediately following stressful life events: a Cox’s hierarchical regression. Thorax. 2004;59(12):1046-1051. [CrossRef] [PubMed]
 
Kaugars AS, Klinnert MD, Bender BG. Family influences on pediatric asthma. J Pediatr Psychol. 2004;29(7):475-491. [CrossRef] [PubMed]
 
Wood BL, Miller BD, Lim J, et al. Family relational factors in pediatric depression and asthma: pathways of effect. J Am Acad Child Adolesc Psychiatry. 2006;45(12):1494-1502. [CrossRef] [PubMed]
 
Szefler SJ, Baker JW, Uryniak T, Goldman M, Silkoff PE. Comparative study of budesonide inhalation suspension and montelukast in young children with mild persistent asthma. J Allergy Clin Immunol. 2007;120(5):1043-1050. [CrossRef] [PubMed]
 
Adams RJ, Wilson DH, Taylor AW, et al. Psychological factors and asthma quality of life: a population based study. Thorax. 2004;59(11):930-935. [CrossRef] [PubMed]
 
Scott KM, Von Korff M, Ormel J, et al. Mental disorders among adults with asthma: results from the World Mental Health Survey. Gen Hosp Psychiatry. 2007;29(2):123-133. [CrossRef] [PubMed]
 
Mancuso CA, Peterson MG, Charlson ME. Effects of depressive symptoms on health-related quality of life in asthma patients. J Gen Intern Med. 2000;15(5):301-310. [CrossRef] [PubMed]
 
Katon WJ, Richardson L, Lozano P, McCauley E. The relationship of asthma and anxiety disorders. Psychosom Med. 2004;66(3):349-355. [CrossRef] [PubMed]
 
Mogensen N, Larsson H, Lundholm C, Almqvist C. Association between childhood asthma and ADHD symptoms in adolescence—a prospective population-based twin study. Allergy. 2011;66(9):1224-1230. [CrossRef] [PubMed]
 
Long-term effects of budesonide or nedocromil in children with asthma. The Childhood Asthma Management Program Research Group. N Engl J Med. 2000;343(15):1054-1063. [CrossRef] [PubMed]
 
Pauwels RA, Pedersen S, Busse WW, et al;; START Investigators Group START Investigators Group. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet. 2003;361(9363):1071-1076. [CrossRef] [PubMed]
 
Chen E, Hanson MD, Paterson LQ, Griffin MJ, Walker HA, Miller GE. Socioeconomic status and inflammatory processes in childhood asthma: the role of psychological stress. J Allergy Clin Immunol. 2006;117(5):1014-1020. [CrossRef] [PubMed]
 
Liu LY, Coe CL, Swenson CA, Kelly EA, Kita H, Busse WW. School examinations enhance airway inflammation to antigen challenge. Am J Respir Crit Care Med. 2002;165(8):1062-1067. [PubMed]
 
Rosenkranz MA, Busse WW, Johnstone T, et al. Neural circuitry underlying the interaction between emotion and asthma symptom exacerbation. Proc Natl Acad Sci U S A. 2005;102(37):13319-13324. [CrossRef] [PubMed]
 
Barnett SB, Nurmagambetov TA. Costs of asthma in the United States: 2002-2007. J Allergy Clin Immunol. 2011;127(1):145-152. [CrossRef] [PubMed]
 
Johnston SL, Pattemore PK, Sanderson G, et al. Community study of role of viral infections in exacerbations of asthma in 9-11 year old children. BMJ. 1995;310(6989):1225-1229. [CrossRef] [PubMed]
 
Johnston NW, Johnston SL, Duncan JM, et al. The September epidemic of asthma exacerbations in children: a search for etiology. J Allergy Clin Immunol. 2005;115(1):132-138. [CrossRef] [PubMed]
 
Boulet LP, Cartier A, Thomson NC, Roberts RS, Dolovich J, Hargreave FE. Asthma and increases in nonallergic bronchial responsiveness from seasonal pollen exposure. J Allergy Clin Immunol. 1983;71(4):399-406. [CrossRef] [PubMed]
 
Green RM, Custovic A, Sanderson G, Hunter J, Johnston SL, Woodcock A. Synergism between allergens and viruses and risk of hospital admission with asthma: case-control study.. [published correction appears inBMJ. 2002;324(7346):1131]. BMJ. 2002;324(7340):763. [CrossRef] [PubMed]
 
O’Byrne PM, Barnes PJ, Rodriguez-Roisin R, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care Med. 2001;164(8 Pt 1):1392-1397. [PubMed]
 
O’Byrne PM, Pedersen S, Lamm CJ, Tan WC, Busse WW; START Investigators Group START Investigators Group. Severe exacerbations and decline in lung function in asthma.. [published correction appears inAm J Respir Crit Care Med. 2010;182(7):983-984]. Am J Respir Crit Care Med. 2009;179(1):19-24. [CrossRef] [PubMed]
 
Talbot TR, Hartert TV, Mitchel E, et al. Asthma as a risk factor for invasive pneumococcal disease. N Engl J Med. 2005;352(20):2082-2090. [CrossRef] [PubMed]
 
Schmidt M, Sun G, Stacey MA, Mori L, Mattoli S. Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma. J Immunol. 2003;171(1):380-389. [PubMed]
 
Saunders R, Siddiqui S, Kaur D, et al. Fibrocyte localization to the airway smooth muscle is a feature of asthma. J Allergy Clin Immunol. 2009;123(2):376-384. [CrossRef] [PubMed]
 
Ernst P, Gonzalez AV, Brassard P, Suissa S. Inhaled corticosteroid use in chronic obstructive pulmonary disease and the risk of hospitalization for pneumonia. Am J Respir Crit Care Med. 2007;176(2):162-166. [CrossRef] [PubMed]
 
Singh S, Amin AV, Loke YK. Long-term use of inhaled corticosteroids and the risk of pneumonia in chronic obstructive pulmonary disease: a meta-analysis. Arch Intern Med. 2009;169(3):219-229. [CrossRef] [PubMed]
 
O’Byrne PM, Pedersen S, Carlsson LG, et al. Risks of pneumonia in patients with asthma taking inhaled corticosteroids. Am J Respir Crit Care Med. 2011;183(5):589-595. [CrossRef] [PubMed]
 
Brassard P, Suissa S, Kezouh A, Ernst P. Inhaled corticosteroids and risk of tuberculosis in patients with respiratory diseases. Am J Respir Crit Care Med. 2011;183(5):675-678. [CrossRef] [PubMed]
 
Barouky R, Badet M, Denis MS, Soubirou JL, Philit F, Guerin C. Inhaled corticosteroids in chronic obstructive pulmonary disease and disseminated aspergillosis. Eur J Intern Med. 2003;14(6):380-382. [CrossRef] [PubMed]
 
Sy ML, Chin TW, Nussbaum E. Pneumocystis carinii pneumonia associated with inhaled corticosteroids in an immunocompetent child with asthma. J Pediatr. 1995;127(6):1000-1002.
 
Kwon HL, Triche EW, Belanger K, Bracken MB. The epidemiology of asthma during pregnancy: prevalence, diagnosis, and symptoms. Immunol Allergy Clin North Am. 2006;26(1):29-62. [CrossRef] [PubMed]
 
Chambers K. Asthma education and outcomes for women of childbearing age. Case Manager. 2003;14(6):58-61. [CrossRef] [PubMed]
 
Enriquez R, Wu P, Griffin MR, et al. Cessation of asthma medication in early pregnancy. Am J Obstet Gynecol. 2006;195(1):149-153. [CrossRef] [PubMed]
 
Sugai K, Ito M, Tateishi I, Funabiki T, Nishikawa M. Neonatal periventricular leukomalacia due to severe, poorly controlled asthma in the mother. Allergol Int. 2006;55(2):207-212. [CrossRef] [PubMed]
 
Murphy VE, Namazy JA, Powell H, et al. A meta-analysis of adverse perinatal outcomes in women with asthma. BJOG. 2011;118(11):1314-1323. [CrossRef] [PubMed]
 
Breton MC, Beauchesne MF, Lemière C, Rey E, Forget A, Blais L. Risk of perinatal mortality associated with asthma during pregnancy: a 2-stage sampling cohort study. Ann Allergy Asthma Immunol. 2010;105(3):211-217. [CrossRef] [PubMed]
 
Blais L, Kettani FZ, Elftouh N, Forget A. Effect of maternal asthma on the risk of specific congenital malformations: a population-based cohort study. Birth Defects Res A Clin Mol Teratol. 2010;88(4):216-222. [PubMed]
 
Gordon M, Niswander KR, Berendes H, Kantor AG. Fetal morbidity following potentially anoxigenic obstetric conditions. VII. Bronchial asthma. Am J Obstet Gynecol. 1970;106(3):421-429. [PubMed]
 
Gelber M, Sidi Y, Gassner S, et al. Uncontrollable life-threatening status asthmaticus—an indicator for termination of pregnancy by cesarean section. Respiration. 1984;46(3):320-322. [CrossRef] [PubMed]
 
Bracken MB, Triche EW, Belanger K, Saftlas A, Beckett WS, Leaderer BP. Asthma symptoms, severity, and drug therapy: a prospective study of effects on 2205 pregnancies. Obstet Gynecol. 2003;102(4):739-752. [CrossRef] [PubMed]
 
Murphy VE, Clifton VL, Gibson PG. Asthma exacerbations during pregnancy: incidence and association with adverse pregnancy outcomes. Thorax. 2006;61(2):169-176. [CrossRef] [PubMed]
 
Blais L, Forget A.. Asthma exacerbations during the first trimester of pregnancy and the risk of congenital malformations among asthmatic women. J Allergy Clin Immunol. 2008;121(6):1379-1384.
 
Breton MC, Beauchesne MF, Lemière C, Rey É, Forget A, Blais L. Risk of perinatal mortality associated with inhaled corticosteroid use for the treatment of asthma during pregnancy. J Allergy Clin Immunol. 2010;126(4):772-777.-, e2. [CrossRef] [PubMed]
 
Schatz M, Dombrowski MP, Wise R, et al;; Maternal-Fetal Medicine Units Network, The National Institute of Child Health and Development Maternal-Fetal Medicine Units Network, The National Institute of Child Health and Development; National Heart, Lung and Blood Institute National Heart, Lung and Blood Institute. The relationship of asthma medication use to perinatal outcomes. J Allergy Clin Immunol. 2004;113(6):1040-1045. [CrossRef] [PubMed]
 
Schatz M, Zeiger RS, Harden K, Hoffman CC, Chilingar L, Petitti D. The safety of asthma and allergy medications during pregnancy. J Allergy Clin Immunol. 1997;100(3):301-306. [CrossRef] [PubMed]
 
Källén B, Otterblad Olausson P. Use of anti-asthmatic drugs during pregnancy. 3. Congenital malformations in the infants. Eur J Clin Pharmacol. 2007;63(4):383-388. [CrossRef] [PubMed]
 
Blais L, Beauchesne MF, Rey E, Malo JL, Forget A. Use of inhaled corticosteroids during the first trimester of pregnancy and the risk of congenital malformations among women with asthma. Thorax. 2007;62(4):320-328. [CrossRef] [PubMed]
 
Hviid A, Mølgaard-Nielsen D. Corticosteroid use during pregnancy and risk of orofacial clefts. CMAJ. 2011;183(7):796-804. [PubMed]
 
Blais L, Beauchesne MF, Lemière C, Elftouh N. High doses of inhaled corticosteroids during the first trimester of pregnancy and congenital malformations. J Allergy Clin Immunol. 2009;124(6):1229-1234. [CrossRef] [PubMed]
 
Lin S, Munsie JP, Herdt-Losavio ML, et al;; National Birth Defects Prevention Study National Birth Defects Prevention Study. Maternal asthma medication use and the risk of gastroschisis. Am J Epidemiol. 2008;168(1):73-79. [CrossRef] [PubMed]
 
Park-Wyllie L, Mazzotta P, Pastuszak A, et al. Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies. Teratology. 2000;62(6):385-392. [CrossRef] [PubMed]
 
National Heart, Lung, and Blood InstituteNational Heart, Lung, and Blood Institute; National Asthma Education and Prevention Program Asthma and Pregnancy Working Group National Asthma Education and Prevention Program Asthma and Pregnancy Working Group. NAEPP expert panel report. Managing asthma during pregnancy: recommendations for pharmacologic treatment-2004 update. J Allergy Clin Immunol. 2005;115(1):34-46. [CrossRef] [PubMed]
 
Bakhireva LN, Jones KL, Schatz M, et al;; Organization of Teratology Information Specialists Collaborative Research Group Organization of Teratology Information Specialists Collaborative Research Group. Safety of leukotriene receptor antagonists in pregnancy. J Allergy Clin Immunol. 2007;119(3):618-625. [CrossRef] [PubMed]
 
Sarkar M, Koren G, Kalra S, et al. Montelukast use during pregnancy: a multicentre, prospective, comparative study of infant outcomes. Eur J Clin Pharmacol. 2009;65(12):1259-1264. [CrossRef] [PubMed]
 
Schatz M, Dombrowski MP. Clinical practice. Asthma in pregnancy. N Engl J Med. 2009;360(18):1862-1869. [CrossRef] [PubMed]
 
Rabe KF, Adachi M, Lai CK, et al. Worldwide severity and control of asthma in children and adults: the global asthma insights and reality surveys. J Allergy Clin Immunol. 2004;114(1):40-47. [CrossRef] [PubMed]
 
Chapman KR, Boulet LP, Rea RM, Franssen E. Suboptimal asthma control: prevalence, detection and consequences in general practice. Eur Respir J. 2008;31(2):320-325. [CrossRef] [PubMed]
 
Williams LK, Joseph CL, Peterson EL, et al. Patients with asthma who do not fill their inhaled corticosteroids: a study of primary nonadherence. J Allergy Clin Immunol. 2007;120(5):1153-1159. [CrossRef] [PubMed]
 
Agertoft L, Pedersen S. Effect of long-term treatment with inhaled budesonide on adult height in children with asthma. N Engl J Med. 2000;343(15):1064-1069. [CrossRef] [PubMed]
 
Kelly HW, Van Natta ML, Covar RA, Tonascia J, Green RP, Strunk RC; CAMP Research Group CAMP Research Group. Effect of long-term corticosteroid use on bone mineral density in children: a prospective longitudinal assessment in the childhood Asthma Management Program (CAMP) study. Pediatrics. 2008;122(1):e53-e61. [CrossRef] [PubMed]
 
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