Abstract
Pregnancy is a unique state requiring alterations in maternal physiology to accommodate the growing fetus. Whilst the maternal immune system is normally well adept at performing this task, the presence of immune disorders, such as asthma, often lead to pregnancy-related complications affecting both mother and baby. Australia has a high prevalence of asthma; with approximately 12% of pregnant women reported to have current asthma. Poor control of asthma is of far greater risk than the use of asthma medications. Being able to identify complications associated with asthma during pregnancy is of great importance in providing appropriate asthma management and medical care to these pregnant women, which may have lifelong consequences for their offspring.
Maternal pregnancy complications associated with asthma
It is now well documented that maternal asthma is associated with a number of complications during pregnancy. These include medical intervention during delivery, adverse perinatal outcomes and maternal complications including gestational diabetes, pregnancy-induced hypertension and pre-eclampsia. Several recent studies have particularly focused on adverse maternal outcomes. For example, in 2010, MacMullen
A South Australian study of all singleton pregnancies between 1999 and 2008 found that compared with non-asthmatic non-smokers, asthmatic non-smokers had an increased odds of hypertensive disorders (aOR: 1.31; 95% CI: 1.21–1.41), gestational diabetes (aOR: 1.33; 95% CI: 1.20–1.48), urinary tract infections (aOR: 1.16;95% CI: 1.40–1.79) and caesarean section (aOR 1.16, 95% CI: 1.10–1.24) [4]. Data published from a systematic review and meta-analysis of literature from 1975 to 2012 [5] found that women with asthma were at increased risk of caesarean section (RR: 1.31; 95% CI: 1.22–1.39), driven by a twofold significantly increased risk of elective C section (RR: 2.14; 95% CI: 1.16–3.95), but no increased risk of emergency C section (RR: 1.03; 95% CI: 0.84–1.26). In addition, in this review, women with moderate to severe asthma were at greater risk than women with mild asthma of both C section (RR: 1.19; 95% CI: 1.09–1.31) and gestational diabetes (RR: 1.19; 95% CI: 1.06–1.33). Encouragingly, the provision of active management reduced the risk of gestational diabetes to a non-significant level compared with women without asthma, suggesting the beneficial effects of appropriate asthma management in pregnancy [5].
In Quebec, Blais
Exacerbations of asthma during pregnancy
Asthma exacerbations or fare-ups are characterized by acute or sub-acute episodes of shortness of breath, wheeze, cough or chest tightness, which worsen progressively and are responsible for most of the healthcare expenditure, morbidity and mortality of asthma. Asthma exacerbations constitute one of the most important risk factors for maternal and fetal complications and the rapid identification and treatment of exacerbations during pregnancy is essential for both maternal and fetal well-being [7]. Exacerbations are the major clinical problem observed in pregnant women with asthma, and our previous studies have indicated that between 33 [8] and 45% [9] of pregnant women with asthma have asthma exacerbations requiring medical intervention (hospitalization, emergency department presentation, unscheduled doctor visit or course of oral corticosteroids for asthma) during pregnancy (Figure 1) [8–10]. In a study where exacerbations were examined retrospectively by examining clinical notes, 33% of women had an exacerbation, with rates differing significantly based on initial asthma severity. Similarly to previous work conducted in the USA [11], women with severe asthma had the highest rate of exacerbations (65%; 95% CI: 52–78.6) compared with women with moderate asthma (47%; 95% CI: 30.3–63.8) or mild asthma (8%; 95% CI: 1.3–14.6). In our prospective cohort study where women attended clinical visits three-times during pregnancy and were regularly followed by phone to assess exacerbations, 45% of women had an exacerbation during pregnancy [9]. Exacerbations were more frequent in current smokers (52%) and ex-smokers (48%) compared with never smokers (35%), and an adjusted linear regression model found that current smoking was associated with higher asthma control questionnaire (ACQ) [12] score during exacerbations, indicating that exacerbations in smokers are symptomatically worse than never smokers. The Managing Asthma in Pregnancy study tested the use of inflammation-based management in pregnant women, using the non-invasive marker of airway eosinophilia, fractional exhaled nitric oxide (FENO), to make adjustments in inhaled corticosteroid (ICS) treatment [10]. The control group had treatment adjustments made based on symptoms and lung function alone, while the intervention group had treatment adjustments made according to FENO (for ICS dose) as well as symptoms and lung function (for long acting beta agonist, LABA use). Similar to our previous cohorts, exacerbations requiring medical intervention occurred in 41% of women in the control group, while the exacerbation rate was significantly reduced by FENO-based management, with only 25% of women in this group having an exacerbation requiring medical intervention (Figure 1) [8–10].
Exacerbations of asthma requiring medical intervention in different studies of asthma during pregnancy.
Exacerbations in pregnancy have adverse consequences for both mother and baby. A systematic review of the literature and meta-analysis published in 2006 demonstrated that women with exacerbations during pregnancy are 2.54 times more likely to have a low birth weight baby compared with women without asthma [13]. More recent data demonstrated a threefold increased risk of low birth weight among women with exacerbations during pregnancy, compared with women without exacerbations during pregnancy (RR: 3.02; 95% CI: 1.87–4.89) [14]. In addition, the use of oral corticosteroids carries increased risks for preterm delivery (RR: 1.51; 95% CI: 1.15–1.98) and low birth weight (RR: 1.41; 95% CI: 1.04–1.93), although the risks are lower than for exacerbations themselves. It is thought that an exacerbation is a greater risk to the fetus than the use of medication to treat it [15].
Risk factors for exacerbations during pregnancy
Numerous etiologies or triggers are responsible for the development of asthma exacerbations. These include exposure to inhaled allergens such as dust mite, cockroach dander, pollens, fungi and air pollutants, medications (e.g., aspirin), occupational sensitizers and respiratory viral infections. Exposure to triggers like exercise, cold air, weather changes and emotional responses also worsen asthma symptoms but their role in severe exacerbations is not clear. Whilst certain factors seem to play key roles, it is likely that a combination of factors can act together to potentiate the exacerbations. During pregnancy, certain factors are particularly important for increasing the risk of severe exacerbations, including smoking, obesity and respiratory virus infections, as well as underuse of medications (discussed below).
Smoking is an important risk factor for inducing asthma symptoms and according to the 2007–08 National Health Survey, there is a higher prevalence of smoking amongst adult females compared with males, and amongst females with asthma compared with females without asthma [16]. There appears to be an increased prevalence of smoking in Australian females with asthma even during pregnancy as evidenced by a retrospective study conducted in 2009 in which 1944 pregnant women with asthma and 13,977 pregnant women without asthma were included [17]. In this study, 34% of pregnant asthmatics smoked during pregnancy compared with 28% of non-asthmatics (p < 0.001). Similar results were obtained in a smaller prospective study published the following year, where women attended clinical visits three-times during pregnancy and were regularly followed by phone to assess exacerbations. In this study, 34% of pregnant asthmatics smoked during pregnancy, compared with 15% of pregnant women without asthma [9]. In addition, exacerbations were more frequent and more severe in current smokers compared with never smokers [9].
A much larger retrospective cohort study which was based on medical record data from 223,512 pregnant women from 12 clinical centers across the US also identified a higher rate of smoking amongst pregnant women with asthma compared with non-asthmatic pregnant women (12.2% vs 6.2%, p < 0.0001) [2]. Not only does smoking increase maternal asthma severity, but independently of asthma, maternal smoking results in a number of adverse outcomes for the infant including low birth weight [3]. Given the high prevalence of asthma and smoking during pregnancy, the increased risk of more severe exacerbations that lead to poor health outcomes for mother and child, which results from smoking, this is a particular problem that needs to be addressed to prevent the vicious cycle in which the cause becomes the effect.
Studies have shown that obesity increases the risk for asthma exacerbations [18]. This interrelationship between obesity and asthma is likely due to both physiological mechanisms (e.g., altered lung volume) and immune mechanisms (e.g., increased inflammation), factors observed in both asthma and obesity [19]. Several recent studies have also identified increased obesity in pregnant asthmatic women. The retrospective cohort study conducted by Mendola
Respiratory viruses represent the most significant risk factor for inducing exacerbations in both adults and children with asthma. With the use of PCR-based viral diagnostics it has been found that human rhinoviruses (HRVs) and influenza are the most common respiratory viruses to infect people with asthma and induce asthma exacerbations. In a recent prospective cohort study of asthma exacerbations during pregnancy, HRV and influenza were found to be amongst the most common viruses detected in nasal or throat swabs in these samples [20]. One-third of the PCR confirmed respiratory virus induced colds in pregnant asthmatic women were associated with an exacerbation requiring medical intervention and another third were associated with loss of asthma control [20].
Viral infections during pregnancy
Rhinovirus infection in pregnancy
Whilst HRV infection usually results in the common cold, for an asthmatic, infection with this respiratory virus represents one of the most potent triggers for an asthma exacerbation [22]. During pregnancy, asthmatics are more likely to experience increased symptom severity following respiratory viral infection, and show increased susceptibility to infection compared with pregnant non-asthmatics. This was observed in a retrospective study where 69% of women with severe asthma and 31% of women with mild or moderate asthma developed a viral infection during pregnancy, compared with 5% of the pregnant non-asthmatics [5,23]. In an Australian prospective cohort study, which included 146 pregnant asthmatic women, it was found that 43% of all asthma exacerbations requiring medical intervention occurred during winter and 34% were associated with self-reported respiratory virus infection [8]. Increased susceptibly to respiratory virus infection was also observed in a more recent prospective cohort study, where the percentage of colds was compared in pregnant women with and without asthma [20]. In this study the common cold questionnaire was used to assess nasal, chest and throat symptoms. A total of 71% of pregnant asthmatic women experienced a questionnaire-detected cold during pregnancy compared with 46% of non-asthmatic pregnant women (RR: 1.83; 95% CI: 1.39–2.41; p < 0.0001). These pregnant asthmatic women self-reported more colds both prospectively during pregnancy, and retrospectively for early pregnancy and during the first 6 months postpartum. In this study, nasal and throat swabs collected during colds were analyzed to determine the respiratory viruses responsible. HRV was the most common isolate to cause colds in pregnant asthmatics (38.5%) and pregnant non-asthmatics (44.8%), followed by human metapneumovirus (23.1% of infections in asthmatics, 17.2% of infections in non-asthmatics) [20].
Influenza infection in pregnancy Influenza is the most common respiratory virus found to cause severe illness in ‘high risk groups’ including pregnant women and adults with asthma [24,25]. Pregnant women are considered a high-risk group for influenza infections, especially during influenza pandemics, where pregnant women are reported to have an increased risk of influenza-induced illness, leading to increased rates of hospitalization, emergency department presentation and increased influenza-induced mortality rates, compared with non-pregnant women. For example, during the outbreak of the 1918 Spanish fu, approximately 50% of all infected pregnant women developed pneumonia, with an overall case mortality rate of 27% [26]. Similarly, in the first outbreak of the 1957 Asian influenza pandemic, pregnant women had a ninefold increased risk of influenza-induced pneumonia, compared with non-pregnant women [27], and 50% of all deaths in women of reproductive age occurred in pregnant women [28]. The rate of hospital admission for pregnant women was higher than in the general population, with 0.32 per 100,000 pregnant women, (95% CI: 0.13–0.52) compared with 0.076 per 100,000 general population (95% CI: 0.07–0.09) [29]. Following infection with H1N1pdm09, pregnant women were more likely to report shortness of breath compared with non-pregnant women of similar age (RR: 1.7; 95% CI: 1.0–2.7) and up to 97% of pregnant women infected with H1N1pdm09 presented with febrile illness that developed into pneumonia, and resulted in acute respiratory distress syndrome [29]. Pregnant women were also found to constitute over 13% of all mortality cases reported from H1N1pdm09 infections [29].
Whilst pregnancy can increase the risk for influenza-induced morbidity and mortality, the presence of respiratory co-morbidities, including asthma, may further complicate influenza infections during pregnancy. As can be expected, pregnancy and asthma were amongst the most prevalent risk factors for severe influenza-related illness during the 2009 H1N1 pandemic [24,25]. One study, which sought to determine the patient demographics, illness severity and risk indicators for infection with H1N1pdm09, found that 81% of patients were females, and in patients presenting with influenza-induced illness, pregnancy and asthma were amongst the highest co-morbidities (34.8 and 39.5%, respectively) [25].
Altered maternal immunity during respiratory virus infections
Many alterations have been identified in asthmatic immunity and research is underway to understand how respiratory viruses may further alter the immune response in asthmatics. It is well established that severe asthma exacerbations frequently occur during pregnancy and are caused by respiratory viruses; however, research is just now beginning to understand the immune response of pregnant women during respiratory virus infections and the further complications in immunity that arise with asthma as co-morbidity.
Studies of peripheral blood mononuclear cells (PBMCs) isolated from pregnant women showed a significantly attenuated innate immune response following infection with HRV43, HRV1B [30] and H1N1pdm09 [31]. PBMCs from pregnant women with asthma also had a significantly altered innate response (measured as IFN-α and IFN-Λ release) and this response was worsened in PBMCs isolated from pregnant women experiencing a current asthma exacerbation [30]. Another recent study showed that these alterations in the innate maternal immune response during pregnancy following respiratory virus infection were associated with changes in key antiviral cells (dendritic cells and CD8 T cells) [32]. H1N1pdm09 was capable of inducing changes in these cells during pregnancy which prevented the maternal immune system from mounting a sufficient antiviral response against the virus; however, blocking this cellular activity restored maternal immunity [32].
Another paper published by Vanders
Management of asthma during pregnancy
According to the 2008 National Asthma Education and Prevention Program (NAEPP) guidelines [38], the goals of asthma therapy include preventing chronic day and night symptoms, maintaining optimal pulmonary function and normal activities, preventing exacerbations, providing therapies that result in minimal or no adverse side effects, and providing satisfactory patient care [38]. In addition to these goals, during pregnancy, the ultimate goal of asthma therapy is the need to maintain fetal oxygenation by preventing maternal hypoxic episodes [39]. To achieve all of these goals requires correct assessment and monitoring based on the presenting clinical symptoms, patient education and correct application of pharmacologic treatments, as well as controlling for known factors that may contribute to increased disease severity or a loss of asthma control [38].
Asthma assessment is primarily based upon the assessment of clinical symptoms, such as cough, wheeze, shortness of breath and chest tightness, and the measurement of lung function using spirometry. Depending on the level of the asthma control and severity at the time of assessment, a step-by-step plan can be followed that allows for rapid identification of any deterioration in asthma and the appropriate measures required to return to a controlled state [7]. For asthmatics, including pregnant women, a stepwise approach is taken to treat asthma symptoms and return asthma control and each step involves intermittent use of a reliever medication, together with an ICS of appropriate dose, often in combination with an LABA or an alternative treatment. Achieving good asthma control means preventing day-to-day symptoms and exacerbations, and currently pharmacologic treatment is the mainstay for effective asthma control.
Asthma medication can be broadly classified as reliever or controller based upon the speed and mode of action of the drug. The NAEPP recommends that pregnant women take short- or long-acting beta agonists (SABAs or LABAs) as well as inhaled steroids to prevent worsening of asthma symptoms [15]. A common concern of pregnant women with asthma is that asthma medication may be harmful to the fetus. Using a 10 cm visual analog scale, where 0 cm represented no perceived risk and 10 cm represented major risk (e.g., birth defects), Powell
Exacerbations in pregnancy should be treated as for non-pregnant adults. However, there has been recent evidence from studies in emergency departments that pregnant women with asthma were less likely to receive oral steroid treatment for their exacerbations compared with non-pregnant women with asthma [42]. In a retrospective study conducted in 2011, which compared emergency department treatment for acute asthma exacerbations in 123 pregnant asthmatic women and 123 non-pregnant asthmatic women, it was found that 72.4% of non-pregnant asthmatics were treated with oral corticosteroids (OCS), compared with only 50.8% of pregnant asthmatics (p = 0.001), whilst at discharge, 41% of pregnant asthmatics were prescribed OCS compared with 69.2% of non-pregnant asthmatics (p < 0.001) [42]. Interestingly, the rate of representation to the emergency department within a 2-week period was significantly higher in the pregnant asthmatics (9.7% compared with 2.5% of non-pregnant asthmatics, p = 0.026).
Multidisciplinary management of asthma during pregnancy
Multidisciplinary management is a recommended approach during pregnancy [15]. A recently published randomized controlled trial tested a multidisciplinary approach against usual care in 60 pregnant women with asthma [43]. The monthly, pharmacist-led intervention involved provision of education, including education about self-monitoring strategies, regular monitoring of asthma control, and collaboration between the pharmacist and family physician for step-up of ICS therapy when required. The intervention group had a statistically and clinically significant improvement in asthma control after 6 months [43]. Another Australian randomized controlled trial (RCT) is currently testing a similar approach in 378 women, which involves a nurse-led intervention in the antenatal clinic setting, with exacerbations as the primary outcome [44].
Inflammation-based management of asthma during pregnancy
Recently, an Australian-based study found that asthma management using the fraction of exhaled nitric oxide (FENO) as a measure of airway inflammation was an effective method of reducing the number of exacerbations during pregnancy in women who were non-smokers [10]. This was a double-blind, parallel-group, randomized controlled trial conducted within two antenatal clinics in Australia, and consisted of 111 pregnant women in the FENO group and 109 pregnant women in the control group, randomized prior to 22 weeks gestation. Women received monthly visits, where asthma self-management education was provided either by an asthma nurse, or a midwife trained in asthma education. At these visits, current treatments (ICS and LABA) were assessed and adjusted based upon the asthma control questionnaire (ACQ) for the control group (as a measure of symptoms and lung function) [45], or by FENO (as a measure of eosinophilic airway inflammation) and the ACQ (as a measure of symptoms), for the active intervention group. When FENO was >29 ppb, an increase in ICS was considered, whilst <16 ppb resulted in a decrease in the dose of ICS. When symptoms remained uncontrolled, LABA was added. The researchers found that the rate of exacerbations was lower in the FENO group compared with the controls (0.288 exacerbations/pregnancy vs 0.615 exacerbations/pregnancy; incidence rate ratio 0.496 (95% CI: 0.325, 0.755, p = 0.001). A reduction in the rate of neonatal hospitalizations was also observed in the FENO group compared with controls (8% vs 17%, p = 0.046) [10]. Another important outcome was that the treatment profile was altered by FENO-based management, with women more likely to be prescribed inhaled steroids, but at a lower mean dose. Previous studies have also showed the benefit of using FENO as a management strategy in non-pregnant chronic asthmatics. In a single-blinded, placebo-controlled trial, 97 chronic asthmatic patients were randomized; n = 46 in the FENO group and n = 48 in the control group [46]. They found that the dose of ICS (fluticasone) was lower in the FENO group compared with the control group (370 μg/day, [95% CI: 263–477] vs 641 μg/day [95% CI: 526–756], p = 0.003) as was the rate of exacerbations (0.49 episodes/patient/year, [95% CI: 0.20–0.78] vs 0.90 episodes/patient/year [95% CI: 0.31–1.49]) [46]. Measuring FENO gives an estimate of the level of steroid-responsive eosinophilic airway inflammation, and given the ease with which measurements of FENO can be made, this may be a particularly useful management strategy that could be implemented in the antenatal clinic setting, for maintaining asthma control and preventing asthma exacerbations, using the minimal effective dose of ICS.
Conclusion
Asthma during pregnancy represents a significant health concern since numerous maternal and fetal complications have been identified, particularly when the asthma is poorly controlled. Asthma exacerbations occur frequently during pregnancy and often result in poor health outcomes. These exacerbations can be attributed to a number of factors including maternal obesity and smoking, and most significantly, by the presence of respiratory virus infections during pregnancy. The alterations in maternal host immunity during pregnancy render the mother with increased risk for severe respiratory virus induced illness which also leads to poor health outcomes for the offspring later in life. Active asthma management plays a critical role in maintaining well-controlled asthma throughout the course of pregnancy and has been shown to improve maternal and fetal outcomes. Correct and consistent use of asthma medications are strongly encouraged throughout the course of pregnancy; however, the development of newer additional asthma management (e.g., FENO-based management) may prove important in ensuring that maternal and fetal health complications are minimized during pregnancy.
Future perspective
The presence of asthma appears to be increasing and since it is now well documented that asthma during pregnancy, especially asthma exacerbations, increase maternal and fetal complications it is of utmost importance that suitable management strategies are in place. As research paves the way in identifying and increasing the awareness of the serious complications associated with asthma, this will drive the development of newer and more efficient management strategies for ensuring optimal asthma control during pregnancy. Many pregnant women as well as medical staff perceive a teratogenic risk of asthma medication use during pregnancy. Encouraging adherence is important since β2 agonists and ICS medication are safe to use during pregnancy. The risk of using oral steroids during an exacerbation is far outweighed by the more serious consequences that result from exacerbations during pregnancy. FENO is an effective way to measure airway inflammation and has been shown to effectively reduce the prevalence of exacerbations during pregnancy.
Executive summary
Increased risk for numerous maternal complications including gestational diabetes and C-section.
Asthma severity and asthma control play an important role in determining the risk for adverse maternal outcomes.
Increased adverse perinatal outcomes include low birth weight, preterm delivery, small-for-gestational-age and preeclampsia.
Exacerbations are the most common clinical problem in pregnant asthmatic women, with 33–45% of these women experiencing at least one exacerbation requiring medical intervention during pregnancy.
Asthma exacerbations have serious adverse perinatal consequences including low birth weight and preterm delivery; however, active asthma management can reduce these consequences.
Risk factors for exacerbations during pregnancy include smoking, obesity and respiratory virus infection.
Human rhinovirus is the most common respiratory virus to infect pregnant asthmatic women and cause asthma exacerbations.
Pregnant women, especially with asthma, are a high-risk group for influenza infections, often leading to intensive care admission, pneumonia and acute respiratory distress syndrome during influenza pandemics.
Pregnant women have an altered antiviral and inflammatory immune response to respiratory virus infection which increases their risk for severe respiratory symptoms following infection.
Active management relies upon maintaining asthma control and reducing exacerbation risk, which requires assessing clinical symptoms and utilizing mainstay pharmacological medications throughout the course of pregnancy.
Active management may not only improve maternal outcomes but reduce the risk of adverse perinatal outcomes.
Financial & competing interests disclosure
R Vanders is supported by an AstraZeneca/TSANZ early career post-doctoral research fellowship. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.