Abstract
Asthma is a heterogeneous disease defined by various respiratory complaints and can present in all age groups. Its hallmarks are variable airflow limitation and chronic airway inflammation. With disease progression, the variability in airflow limitation can become irreversible.
Introduction
Asthma is a heterogeneous disease defined by various respiratory complaints and can present in all age groups. Its hallmarks are variable airflow limitation and chronic airway inflammation. With disease progression, the variability in airflow limitation can become irreversible.
During pregnancy in particular, asthma presents unique management challenges. Furthermore, the degree of asthma control can affect not only the health of the mother, but also that of the fetus. In this chapter we will discuss the epidemiology, clinical presentation, complications and management of asthma during pregnancy.
Prevalence of Asthma during Pregnancy
The World Health Organization estimates that 235 million people worldwide suffer from asthma. In the United States up to 12.5% of the general population is affected by it.1 The prevalence of asthma in pregnancy approximates that of the general population. Asthma has been reported in 8.4–10.5% of pregnant American women.2,3 Two separate reviews of women with singleton births in Australia and Sweden demonstrated an asthma rate of 12% and 9.4%, respectively.4,5 In a single-centre study from Iran, as many as 38.8% of pregnant women with dyspnoea were diagnosed with asthma.6
Clinical Presentation and Diagnosis
When encountered during pregnancy, asthma is most often part of the mother’s past medical history. Historically, asthma control has been quoted to stay stable in one-third, worsen in one-third and improve in one-third of pregnant asthmatic patients.7 However, in reality, pregnancy can have an unpredictable impact on asthma symptoms in different women and can vary from pregnancy to pregnancy as well.8 In cases of de novo presentations while pregnant, the same diagnostic criteria apply as in non-pregnant patients.
Asthma is a clinical diagnosis. Patients can present with dyspnoea, wheeze, chest tightness, cough and other respiratory complaints. Generally, patients have triggers that induce or exacerbate the underlying disease. Often, there is a circadian presentation of clinical symptoms. Concurrently, patients demonstrate variable airflow limitation. This limitation may not be present on screening pulmonary function testing if the patient’s asthma is not active. Bronchodilator testing can assist with identifying variable airflow limitation. FEV1 is not affected by pregnancy, so serial lung function measurements with spirometry and peak flow meter recordings can assist with tracking asthma control. In pregnancy, bronchoprovocation testing is avoided.
Asthma Control and Perinatal Outcomes
Asthma control is essential for the health of the mother and fetus. Guidelines emphasize the importance of optimal asthma control during pregnancy.9 It has been established that poor asthma control is associated with increased risk of pre-eclampsia, perinatal mortality, congenital malformations, pre-term birth and low birth weight.10–12 A Canadian review of asthmatic and non-asthmatic pregnancies from 1992–2002 also suggested that poor maternal asthma control increased the risk of spontaneous abortions.13
Asthma exacerbations during pregnancy correlate with degree of preceding asthma control. Furthermore, differences in geography and socioeconomic factors also affect exacerbation incidence. A 2003 American study noted that 12.6% of mild, 25.7% of moderate and 51.9% of severe asthmatics suffered from exacerbations during pregnancy.14 A South Korean retrospective database review from 2009 to 2013 described the prevalence of asthma exacerbation to be 5.3% in their cohort.15 Another prenatal cohort from a low socioeconomic background in Australia revealed a moderate-to-severe exacerbation rate of 22%.16 Exacerbations were defined similarly in the above-mentioned studies. The criteria grossly included asthma-related hospitalizations, emergency department visits or oral steroid prescriptions.
Interestingly, asthma exacerbations alone during pregnancy have not consistently been linked to adverse fetal events.12 In one prospective limited cohort of pregnant asthmatics, severe exacerbations during pregnancy were linked to increased rate of low birth weight,17 although only among sons. A follow-up meta-analysis found an increase in rate of infant low birth weight in women with severe asthma exacerbations.18 Conversely, in the two aforementioned South Korean and Australian cohorts, asthma exacerbations did not lead to an increase in adverse fetal effects.13,16 Exacerbation severity did not differ between these studies.
The National Asthma Education and Prevention Program (NAEPP), and Global Initiative for Asthma (GINA) guidelines both recommend optimization of asthma control during pregnancy. They note that the risk of poor asthma control to the fetus is greater than possible risks posed by asthma treatment.9,10,19 The management of asthma during pregnancy is similar to the management of the general population with asthma. Inhaled corticosteroids (ICS) are the preferred controller medication, and albuterol (salbutamol) is the preferred short-acting agent.
Despite the presence of guidelines, real-world implementation of asthma treatment during pregnancy can be limited. An analysis of the National Health and Nutrition Examination Survey (NHANES) database reviewed the incidence of prescription medication use among pregnant vs non-pregnant woman. It noted that prescription medication usage fell from 47% among non-pregnant women to 22% in pregnant women. The observed drop in prescriptions occurred across varying classes of medications. Medications of particular interest included in the analysis were albuterol, montelukast, cetirizine and budesonide.20 Literature has also shown that pregnant women presenting to emergency departments with acute asthma are less likely to receive systemic steroids.21,22 Similarly, in the previously mentioned South Korean cohort, a higher rate of pregnant compared to non-pregnant asthmatics were hospitalized for asthma complaints. Yet despite the relative increase in hospitalizations, pregnant asthmatics had fewer outpatient visits and asthma medications prescribed.15
Asthma Management and Medication Use
The goals of asthma symptom control and prevention of exacerbations during pregnancy do not differ from those in the non-pregnant individual.
Inhaled Corticosteroids
The cornerstone of treatment for asthma includes ICS. Low-dose ICS has generally been regarded to be safe in pregnancy. A Swedish registry examined the use of inhaled budesonide in pregnant patients and noted no change in birth weight and length of infants.23 Another North American study demonstrated that ICS did not alter birth weight.24 With increases in asthma severity, the treatment algorithm indicates that medium-to-high dose ICS in combination with long-acting β-agonists (LABA) can be added. Therapy can be further escalated with oral prednisone, immunotherapy and others agents as needed.25
Concerns have been raised regarding the use of high-dose ICS in pregnant patients. A Canadian study evaluated the risk of perinatal mortality in pregnant asthmatics. It found that a subset of patients requiring high-dose ICS had a statistically non-significant increase in risk (OR 1.52, 95% CI, 0.62–3.76).26 Another Canadian analysis comparing birth defects in pregnant asthmatics requiring low-to-moderate- vs high-dose ICS in the first trimester demonstrated a statistically non-significant increase in congenital malformations.27 However, both studies raise the possibility of confounding from underlying asthma severity that necessitated the use of high-dose ICS (see also Chapter 22, Biological and Immunosuppressive Respiratory Therapy in Pregnancy).
Long-acting β-agonists
There are relatively little data on the inclusion of LABA therapy in the treatment of maternal asthma. A comparison study of ICS/LABA combination therapy vs higher doses of ICS monotherapy sought to clarify if the risk of congenital malformations was any different. The subcohorts included low-dose ICS/LABA vs medium-dose ICS, and medium-dose ICS/LABA vs high-dose ICS therapy administered in the first trimester. No difference in the risk of congenital malformations was noted in the two subcohorts for ICS/LABA vs increased-dose ICS.28
In contrast, a systematic review of 21 studies performed in 2014 evaluating the safety of β-agonist use in pregnancy yielded mixed results. Some of the studies demonstrated a significant increase in congenital malformations, while others did not. However, the control group in most of the positive studies included non-asthmatic women, thereby introducing confounding.29 In order to take into account the risk of congenital malformations from the disease itself, the control group would have had to be comprised of pregnant asthmatics not taking β-agonists.
Other Therapy
At times, inhaler therapy alone is inadequate for asthma control in pregnancy. For patients with severe asthma, additive options include leukotriene-receptor antagonists (LTRA), immunotherapy such as omalizumab and systemic prednisone for acute exacerbations. There are studies that have examined the relationship between LTRAs and fetal risks in pregnancy, with the majority of the data focusing specifically on montelukast. Montelukast is considered safe in pregnancy,9 although some literature has noted a relationship between montelukast and an increased risk of congenital malformations. There have also been reported findings of lower infant birth weights.30–32 The authors of these studies have acknowledged that, again, possible confounding due to increased asthma severity may have contributed to their findings. In contrast, zileuton should be avoided in pregnancy.9
In a recent prospective observational study, exposure to omalizumab prior to and during pregnancy was followed-up at 18 months post-delivery for the occurrence of congenital malformations, prematurity, low birth weight and smaller infant size. In this limited study population, these risks were not increased from historical risks noted in the general pregnant asthma population.33
There have been previous concerns about an association between maternal corticosteroid use and congenital orofacial malformations. Older studies have noted an increase in incidence of cleft lip or palate in the infant after maternal first trimester exposure to systemic steroids for various conditions.34–36 However, more recent follow-up data from the National Birth Defect Prevention Study (NBDPS) for all-comers during pregnancy requiring steroids did not note any association between steroid use in pregnancy and cleft lip or palate.37 This absence of association is further supported by contemporary prevalence data from Denmark.38 In addition, a meta-analysis performed in 2013 suggested an increased risk of low birth weight and pre-term delivery with oral steroid use specifically in the context of maternal asthma exacerbations.39
Evidence-based guidelines from NAEPP and GINA recommend appropriate asthma treatment during pregnancy, as poor asthma control during pregnancy can lead to adverse fetal outcomes.9,10,19 Any risks to the fetus due to asthma therapy, including systemic steroids, are outweighed by the consequences of poor asthma control (see also Chapter 22, Biological and Immunosuppressive Respiratory Therapy in Pregnancy).
Co-morbid Conditions and Treatment Challenges
Co-morbidities characterized by dyspnoea, cough and other respiratory complaints during pregnancy can complicate both the diagnosis and treatment of asthma. For example, an array of physiologic changes take place during pregnancy, including increases in cardiac output and minute ventilation. The increase in minute ventilation is attributed to an increase in tidal volume.40 These physiological changes can at times manifest as a sense of dyspnoea (see Chapter 16, Dyspnoea of Pregnancy) and can be confused with asthma.
Gastro-oesophageal reflux disease (GERD) and rhinitis of pregnancy are other masqueraders of asthma. A German study looking at prevalence of GERD in pregnancy found that GERD symptoms progress over the course of pregnancy. Non-pregnant women had a 9.3% prevalence of symptoms, while 26.1% of pregnant women suffered from symptoms in the first trimester. This increased to 51.2% in the third trimester.41 An increase in intra-abdominal pressure due to the gravid uterus and relaxation of lower oesophageal sphincter due to hormonal effects contribute to increased reflux. Treatment includes lifestyle modification and acid suppression therapy. In these instances, patients may not benefit from asthma therapy alone.
Rhinitis of pregnancy is nasal congestion, post-nasal drip, and/or cough without other signs of respiratory tract infection and no underlying atopy. The American College of Chest Physicians clinical practice guidelines distinguishes it from other causes of rhinitis by its onset in pregnancy and subsequent resolution post-partum.42 Incidence of pregnancy-induced rhinitis was noted to be 20% in an Australian cohort.43 A Swedish study found the cumulative incidence of pregnancy-induced rhinitis to be 22%. They also found that the syndrome could appear at any point during pregnancy and resolve within one week of parturition in 76% of women. In this series, co-morbid asthma did not lead to any increase in incidence of pregnancy-induced rhinitis.44 Although post-nasal drip can certainly contribute to asthma symptoms, treatment of asthma alone is unlikely to alleviate rhinitis symptoms.
When GERD and rhinitis present concurrently with asthma they can often lead to further decline in asthma control. Co-morbid rhinitis in particular leads to poorer asthma outcomes among pregnant women. In the previously mentioned Australian cohort, pregnant women with asthma and rhinitis when compared to pregnant women with asthma alone were found to have worse asthma control. Lung function also declined significantly in pregnant women with asthma and rhinitis.43 When these conditions present concomitantly with asthma, their treatment also leads to improved asthma control.
Yet another treatment challenge in the care of pregnant asthmatics involves the variability in care that is available to different subpopulations. There are known ethnic and socioeconomic health disparities in asthma that can impact maternal asthma care as well.45 Carroll et al. found that in a low-income population, pregnant asthmatics who were black had more asthma-related morbidity than whites, with higher rates of rescue corticosteroid use, emergency department visits and inpatient hospitalizations.46 It is likely that racial and socioeconomic barriers relevant to healthcare overall are equally pertinent in prenatal care and can contribute to disparities in maternal asthma outcomes.
The impact of race/ethnicity on obstetrical and neonatal outcomes among women with asthma, however, is relatively understudied. Prior investigations have shown conflicting results.47,48 An analysis of the Healthcare and Utilization Project for deliveries to asthmatic women from 1998 to 1999 suggested inter-racial disparities in outcomes such as pre-term labour, chorioamnionitis and gestational diabetes. These adverse events were higher in minorities than in whites.49 In contrast, a later epidemiologic study found that asthma did not contribute to racial/ethnic disparities in birth complications.48 It is possible that the abundance of competing risks50 and/or under-reporting of complications among non-whites may explain the lack of consistent data demonstrating the differential effects of maternal asthma on the risk of obstetrical and neonatal complications across racial ethnic groups, especially among black women.
Encouragingly, however, among expectant mothers in low-income areas, simply having the diagnosis of asthma can positively impact their desire to overcome traditional barriers to healthcare. One study revealed that asthma was a significant positive co-variate contributing to pregnant women’s efforts to seek out information and educate themselves about their own prenatal care.51 This piqued interest in information-seeking may be an opportunity to capture and educate pregnant patients who may otherwise be at a healthcare disadvantage in order to improve their asthma care and outcomes.
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