Asthma in pregnancy

Abstract

Background:

Asthma is a frequent and potentially life-threatening disease that complicates many pregnancies. There are extensive data with regard to the diagnosis and treatment of asthma during pregnancy. Medical providers require an up-to-date summary of the critical aspects of asthma management during pregnancy.

Objective:

This review aimed to summarize the available data from clinical trials, cohort studies, expert opinions, and guideline recommendations with regard to asthma in pregnancy.

Methods:

A search through PubMed was conducted by using keywords previously mentioned and MeSH (Medical Subject Headings) terminology. Clinical trials, observational studies, expert opinions, guidelines, and other reviews were included. The quality of the studies was assessed, and data were extracted and summarized.

Results:

Asthma worsens in ∼40% of pregnant women, which can be associated with maternal and fetal complications. Physiologic changes in the respiratory, cardiovascular, and immune systems during pregnancy play a critical role in the manifestations of asthma. The diagnosis and the treatment of asthma are similar to that of patients who are not pregnant. Nonetheless, concern for fetal malformations, preterm birth, and low birth weight must be considered when managing pregnant patients with asthma. Importantly, cornerstones of the pharmacotherapy of asthma seem to be safe during pregnancy.

Conclusion:

Asthma in pregnancy is associated with adverse outcomes. Roadblocks to management include associated comorbidities, medication nonadherence, atopy, lack of education, and smoking habits. These need to be acknowledged and addressed for successful asthma management during pregnancy.

Asthma prevalence during pregnancy ranges from 3% to 6%.¹ Among those pregnancies, 19% had severe asthma and 16% had poorly controlled asthma.¹ Furthermore, asthma is one of the most common chronic diseases that complicate pregnancies. However, approximately a fourth of pregnant patients with asthma discontinue their medications due to negative beliefs about safety.^2,3 Due to the extensive list of complications in pregnant patients with asthma and their fetuses, medical providers require an updated summary of key aspects in physiologic changes, diagnosis, and treatment. This review aimed to summarize the most recent data to assist the reader in the diagnosis and treatment of pregnant women with asthma. For this, we have gathered information from clinical trials, observational studies, expert opinions, guidelines, and other reviews. Institutional review board approval was not required.

RELEVANT PHYSIOLOGIC CHANGES DURING PREGNANCY

A myriad of cardiovascular changes occurs in response to increased metabolic demands from the mother and fetus to ensure proper uteroplacental circulation. In the first trimester, there is a diminished peripheral vascular resistance,⁴ with an increased cardiac output⁵ and heart rate.⁴ Also, oxygen and metabolic rate consumption increase by 20%.⁶ Moreover, the respiratory system also undergoes adaptations during pregnancy with significant anatomic and hormonal changes that affect pulmonary function parameters in the mother.⁷ As pregnancy progresses, there is an upward displacement of the diaphragm with an increased lower chest wall circumference and costal angle widening.⁸ As a consequence, expiratory reserve and residual volumes decrease, while tidal volume increases.⁹

In contrast, forced vital capacity and peak expiratory flow do not change.¹⁰ Interestingly, these changes are not associated with a significant deterioration of quality of life.¹¹ In addition, the elevation of progesterone levels, especially at the end of the first trimester, induces hyperventilation and results in a decreased (partial pressure of carbon dioxide; PaCO₂) with transient respiratory alkalosis.¹² Due to these physiologic changes, 60%–70% of pregnant women can experience dyspnea during the first and second trimesters.^12–14 Importantly, compared with pregnant women who are not asthmatic, lung function changes are more pronounced in pregnant women with asthma.

The immune system also changes during pregnancy. For instance, there is a predominant T-helper type 1 (Th1) response in the first trimester with a subsequent shift to a T-helper type 2 (Th2) response in the second and third trimesters.^15,16 The recruitment of specialized immune cells occurs within the decidua on implantation, which mostly contains macrophages, natural killer cells, regulatory T cells (Treg), and dendritic cells, which creates a proinflammatory environment that favors trophoblastic invasion.^17,18 After the first weeks of gestation, there are changes in B-cell populations, including a decrease in total B-cell numbers.^18,19 Among the most significant changes, an increasing regulatory B cell population promotes immune tolerance to avoid fetal rejection.²⁰ Furthermore, there is evidence that Tregs also promote anti-inflammatory conditions during the second trimester.²¹ Interestingly, other studies^22–44 have shown multiple abnormalities in immune cell subgroups of women with asthma during pregnancy. There is an increased number of B cells, memory cells, plasmablasts,²² monocytes, and neutrophils compared with women who are not asthmatic.²³ In addition, the pregnancy-induced increase in Tregs is decreased in asthmatic pregnancy, which may interfere with fetal development and tolerance.²⁴

Hormonal changes during pregnancy also influence the cytokine milieu.²⁵ In particular, the gradual increase of estrogen and progesterone at the end of the first trimester reduces tumor necrosis factor α production, interferon (IFN) γ expression, and natural killer cell activity, facilitating an anti-inflammatory environment.²⁶ In pregnant women with asthma, an abnormally increased Th2 response is present.²⁶ Notably, an observational study in pregnant women found higher levels of interleukin (IL) 4, IL-6, and IFN-γ.²⁷ In addition, a statistically significant negative correlation has been reported between the levels of IL-4 and IFN-γ and maternal peak expiratory flow among pregnant women with asthma.²⁸ Furthermore, asthma during pregnancy increases the circulating level of proinflammatory C5a, which is accompanied by impaired lung function and partly counteracted by the gestation-specific elevation of regulatory complement factor H level.²⁹ Exhaled breath condensate pH is higher in healthy pregnant women compared with their counterparts with asthma, which suggests oxidative inflammation at play in pregnant women with asthma.³⁰ Moreover, studies have also shown an increase in exhaled breath condensate pH during asthma exacerbations.³¹ The physiologic changes during pregnancy are summarized in Table 1.

Table 1.

Summary of physiologic changes during pregnancy

PaCO₂ = ; FVC = forced vital capacity; FEV₁, = forced expiratory volume in the first second of expiration; PEF = peak expiratory flow; PaCO₂ = partial pressure of carbon dioxide.

*From Ref. 12.

#Adapted from Ref. 92.

DIAGNOSIS

Most pregnant women with asthma already have an established diagnosis before gestation. For those who present with respiratory symptoms during pregnancy and without a previous diagnosis of asthma, multiple conditions need to be considered. Importantly, 60% of pregnant women report shortness of breath due to the previously described changes in the pulmonary system.³² However, shortness of breath that impairs functionality and the association with other symptoms such as chest pain, cough, or wheezing warrant further workup. Medical conditions to consider include upper respiratory infections, gastroesophageal reflux disease, pulmonary embolism, pulmonary edema, and asthma.³³

A clinical presentation typical of asthma increases the probability of this condition but is not confirmatory. Importantly, forced vital capacity and forced expiratory volume in the first second do not change during pregnancy.¹⁰ A confirmed parameter of expiratory flow limitation should be met with lung function testing and a bronchodilator test, as referenced in The Working Group on Asthma and Pregnancy Guidelines.³⁴ In addition, asthma severity is classified according to the parameters defined by the National Asthma Education and Prevention Program Working Group on Asthma and Pregnancy as mild, moderate, moderate with additional therapy, and severe (Table 2). This classification considers daytime and nighttime symptoms plus spirometry values and implications for treatment options.^35,36

Table 2.

Asthma severity classification in pregnant women^*

FEV₁, = Forced expiratory volume in the first second of expiration; PEF = peak expiratory flow.

^*Adapted from Ref. 67.

FOLLOW-UP

Asthma's course during pregnancy is highly variable. Retrospective and prospective studies have shown that asthma worsens in a third of patients, improves in a fourth of patients, and remains unchanged in a third of them, with similar disease courses in subsequent pregnancies.³⁷ In addition, asthma severity during pregnancy is similar to the severity observed during the prepregnancy state when these patients continued to use their medications.³⁸ Determinants of low-risk asthma exacerbation are clinically stable asthma, no history of exacerbations, and no necessity of treatment with controller medication because of mild disease.³⁹

Evaluation of asthma control during pregnancy is critical, and it should be assessed by spirometry and validated questionnaires in prenatal visits.⁴⁰ As described in the Global Initiative for Asthma (GINA) recommendations,⁴¹ an assessment of asthma symptom control could be made by questioning the frequency of asthma symptoms, the necessity of short-acting inhaled therapy, and the time of appearance of such symptoms. In addition, numerical questionnaires, e.g., the Asthma Control Test (QualityMetric Incorporated, Johnston), have been used and validated to assess asthma control in pregnant women.^42,43

Other tools to assist asthma control evaluation during follow-up of pregnant patients are being studied. For instance, fractional exhaled nitric oxide (FeNO), was evaluated in a prospective study⁴⁴ in which 111 women were randomly assigned to the FeNO group. An exacerbation rate was lower in the FeNO group than in the control group, with a number needed to treat of six. In the FeNO group, the quality of life was improved.^44,45 As with nonpregnant adults with asthma, further studies are needed to evaluate FeNO-guided treatment.

MATERNAL AND FETAL OUTCOMES

Asthma has been associated with a wide variety of complications and adverse outcomes for mothers in all phases of gestation and among neonates, with a growing prevalence in recent years.⁴⁶ As stated by Kwon et al.,⁴⁷ higher numbers of pregnant women with asthma are driven by an increasing prevalence of asthma among younger pregnant women, likely as a consequence of lifestyle and urbanization changes.^48,49 Some investigators postulate that complications among pregnant women are increasing due to increased obesity, consumption of tobacco products, and a higher prevalence of psychosocial issues.⁵⁰ Some complications reported by observational studies include spontaneous abortion, antepartum and postpartum hemorrhage, placental abruption, gestational diabetes, cesarean section, placenta previa, premature rupture of membranes, preterm birth, a higher risk of a breech presentation, pulmonary embolism, and maternal intensive care unit admission.^51–56

Furthermore, it seems that asthma severity influences the risk of complications because adverse outcomes are more prevalent in pregnant women with moderate-to-severe asthma.⁵² Pregnant women with asthma are also at an increased risk of experiencing transient hypertension of pregnancy, preeclampsia, or eclampsia.⁵⁷ Notably, obesity and weight gain during pregnancy have also been associated with worse outcomes in pregnant patients with asthma, and this relationship seems to increase in a dose-dependent matter.⁵⁸ Maternal asthma is also associated with an increased risk of multiple diseases in the offspring, including infectious, respiratory, cutaneous, and hematologic illnesses,⁵⁹ and childhood asthma.⁶⁰ A higher rate of congenital abnormalities and being small for gestational age have also been noted.⁴⁶ In contrast, another study found no significant association between maternal asthma and birth weight, Apgar scores, or respiratory distress syndrome.⁶¹

TREATMENT

Management of asthma in pregnant patients includes education about the disease, inhaler technique, the importance of adherence independent of risk classification, and management of other associated comorbidities.⁶² It is essential to identify potential roadblocks to adequate asthma management in pregnant women (Fig. 1). A retrospective cohort study of 115,169 pregnant women with asthma recognized a tendency of these patients to decrease their asthma therapy during gestation with a subsequent increase in the rate of exacerbations.⁶³ Furthermore, poor asthma control was observed in pregnant women with lower income, less education, younger age, and a smoking habit.^64,65 Clinicians need to adequately assess concerns about asthma management and perceptions of disease course to ensure proper adherence.⁶⁶

Figure 1.

Comorbidities and socioeconomical factors to consider when managing women with asthma during pregnancy.

Pregnant women with asthma and with associated comorbidities, including atopy, rhinitis, and gastroesophageal reflux disease, require proper management to avoid poor asthma control (Table 3). For instance, atopy treatment needs lifestyle modifications and avoidance of common allergens, including pet dander, pollens, mold, house-dust mite, and cockroaches,⁶⁷ to decrease the probability of asthma exacerbations.⁶⁸ Allergen-specific immunotherapy may be continued if started before conception, but its initiation is contraindicated during pregnancy due to concerns of anaphylaxis.⁶⁹

Table 3.

Comorbidities that can exacerbate asthma during pregnancy

GERD = Gastroesophageal reflux disease; IL = interleukin.

Multiple studies exhibited the association of appropriate asthma control and perception of the disease with multidisciplinary team involvement in the care of pregnant women with asthma.⁷⁰ Interestingly, antenatal asthma management services reduce the risk of exacerbations, persistent uncontrolled asthma, and loss of disease control.^58,71,72 In this regard, a randomized control trial that involved 60 pregnant women with asthma evaluated a multidisciplinary model of care for asthma management, including monitoring, education, and pharmacist-led intervention.⁷³ This study demonstrated a decrease in the rate of asthma exacerbations and improvement in disease control among pregnant women.⁷³

As mentioned in the GINA recommendations,⁴¹ asthma management should consider symptom control and risk reduction when prescribing medication. There is evidence of the importance of controlling asthma exacerbations in pregnant women to avoid substantial morbidity, mortality, and adverse fetal outcomes.^74,75 As such, continuing inhaled therapy during pregnancy outweighs the risks of potential medication adverse effects.^76,77 Medications for pregnant women with asthma include inhaled corticosteroids, leukotriene receptor antagonists, long-acting β₂-agonists, short-acting β₂-agonists, inhaled muscarinic antagonists, and, most recently, biologics.⁴¹ The therapeutic options according to asthma severity are summarized in Table 4.⁴¹

Table 4.

Medications for the management of asthma during pregnancy

ICS = Inhaled corticosteroid; LABA = long-acting β-2 agonist; LRA = leukotriene receptor antagonist; IgE = immunoglobulin E; IL = interleukin; SABA = short-acting β2-agonists.

Medication nonadherence is a critical problem when managing pregnant women with asthma. In a population-based control study⁷⁸ that describes the use of asthma medications during pregnancy, the investigators described that 85% of women with asthma used albuterol, 46% used fluticasone, and 15% used montelukast. Importantly, 70% of women who used inhaled bronchodilators during the preconception period continued their use amid gestation,⁷⁸ with other medications being more frequently discontinued.⁷⁹ Limitations for adequate asthma management include medication safety concerns during pregnancy because women perceive a deleterious effect on the fetus as a reason to discontinue therapy. Importantly, evidence from multiple observational studies has not shown a statistically significant correlation between inhaled therapy and congenital heart defects,⁷⁸ and cleft lip, stillbirth, neonatal hospitalization, respiratory distress syndrome, and neonatal sepsis.⁸⁰ Notably, inhaled corticosteroids do not seem to affect fetal adrenal function.⁸¹

It is also important to note that there is a surge in novel therapies for asthma, including biologics, e.g., omalizumab.⁷⁰ Notably, a prospective cohort study did not demonstrate an increased risk of congenital abnormalities in pregnant women treated with omalizumab.⁷⁰ Nonetheless, because evidence is limited, current guidelines recommend continuing the use of omalizumab in pregnant women treated preconceptionally and not initiating it during pregnancy.⁸² Animal studies and case reports of patients with asthma who received anti–IL-5 biologics and dupilumab during pregnancy suggest that these biologics have a good safety profile.^83–89 Further prospective studies are warranted to investigate the effects of asthma biologics during pregnancy.

Experimental and epidemiologic evidence has revealed increased reactive oxygen species production and inflammation during asthma in pregnancy. Introducing dietary antioxidants might decrease asthma severity,⁹⁰ as demonstrated in some randomized controlled trials that used lycopene and β-carotene as supplements.^91,92 However, interventional studies in pregnant women with asthma are needed to fully elucidate the benefits of antioxidants in this population.⁶²

MANAGEMENT OF ACUTE EXACERBATIONS

Fifty percent of asthma exacerbations during pregnancy occur before 20 weeks of gestation ⁹³ and are associated with adverse obstetric outcomes,⁹⁴ including congenital malformations when severe exacerbations occur during the first trimester,⁹⁵ low birth weight,⁹³ preterm delivery,⁹⁶ preeclampsia, and spontaneous abortion.⁹⁷ Overall, treatment of asthma exacerbations during pregnancy is similar to patients who are not pregnant. First, exacerbation severity should be assessed by measuring expiratory airflow with a peak flow meter. Constant maternal and fetal monitoring must be ensured by using maternal oxygen saturation >95% and fetal heart rate testing; signs of impending respiratory failure must be routinely evaluated.

Special consideration to physiologic changes in the acid-base balance during pregnancy is required when interpreting arterial blood gas results because an apparent normal partial pressure of carbon dioxide (PaCO₂) may signify a more severe respiratory compromise.⁶⁹ Medications should include supplemental oxygen titrated to maintain adequate saturation, short-acting β-agonists, inhaled muscarinic antagonists (e.g., ipratropium bromide), systemic glucocorticoids in oral or intravenous preparations, and adjunct therapies in poor response, including magnesium sulfate and terbutaline.^67,69

PERIPARTUM MANAGEMENT OF ASTHMA

Pregnant patients with asthma have a higher incidence of labor induction with oxytocin and cesarean section rates.⁹⁸ Furthermore, ∼10% of pregnant patients with asthma will have increased symptoms during labor, usually controlled with bronchodilators.⁹⁹ During labor and delivery, asthma therapy should be continued and adequate hydration and analgesia must be provided to avoid complications.³⁵ Generally, labor and delivery management medications are safe with a few exceptions; among them, the prostaglandin F2-α analogs (e.g., carboprost) cause bronchoconstriction in animal studies and are contraindicated in pregnant women with asthma.¹⁰⁰ Also, the use of morphine and meperidine for pain control should be avoided due to the risk of inducing histamine release.⁶⁷

CONCLUSION

Further studies are required to elucidate the pathologic mechanisms involved in pregnant women with asthma. Moreover, additional investigations of the variable behaviors of asthma during gestation and the determinants that influence asthma's severity during pregnancy are warranted. Future directions should also focus on determining the risks of adverse maternal and fetal outcomes associated with specific asthma medications. This is particularly important given the advent of novel biologics for the treatment of asthma.