Asthma in pregnancy

Daniela C. Bravo-Solarte, M.D., Danna P. Garcia-Guaqueta, M.D., and Sergio E. Chiarella, M.D.

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 man-
ifestations 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 preg-
nant 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.
(Allergy Asthma Proc 44:24–34, 2023; doi: 10.2500/aap.2023.44.220077)

A sthma prevalence during pregnancy ranges

from 3% to 6%.1 Among those pregnancies, 19%
had severe asthma and 16% had poorly controlled
reviews. Institutional review board approval was
not required.

asthma.1 Furthermore, asthma is one of the most RELEVANT PHYSIOLOGIC CHANGES DURING
common chronic diseases that complicate pregnan- PREGNANCY
cies. However, approximately a fourth of pregnant A myriad of cardiovascular changes occurs in
patients with asthma discontinue their medications response to increased metabolic demands from the
due to negative beliefs about safety.2,3 Due to the mother and fetus to ensure proper uteroplacental cir-
extensive list of complications in pregnant patients culation. In the first trimester, there is a diminished pe-
with asthma and their fetuses, medical providers ripheral vascular resistance,4 with an increased cardiac
require an updated summary of key aspects in phys- output5 and heart rate.4 Also, oxygen and metabolic
iologic changes, diagnosis, and treatment. This rate consumption increase by 20%.6 Moreover, the re-
review aimed to summarize the most recent data to spiratory system also undergoes adaptations during
assist the reader in the diagnosis and treatment of pregnancy with significant anatomic and hormonal
pregnant women with asthma. For this, we have changes that affect pulmonary function parameters in
gathered information from clinical trials, observatio- the mother.7 As pregnancy progresses, there is an
nal studies, expert opinions, guidelines, and other upward displacement of the diaphragm with an
increased lower chest wall circumference and costal angle
widening.8 As a consequence, expiratory reserve and re-
sidual volumes decrease, while tidal volume increases.9
From the Division of Allergic Diseases, Mayo Clinic, Rochester, Minnesota In contrast, forced vital capacity and peak expiratory
This work was supported by the National Institutes of Health National Institute of
Allergy and Infectious Diseases K08AI141765 grant and the Mayo Clinic Specialized flow do not change.10 Interestingly, these changes are
Center of Research Excellence and Women’s Health Research Center Career not associated with a significant deterioration of qual-
Enhancement Core Award U54AG044170 to S.E. Chiarella
ity of life.11 In addition, the elevation of progesterone
The authors have no conflicts of interest to declare pertaining to this article
No external funding sources reported levels, especially at the end of the first trimester, indu-
Address correspondence to Sergio E. Chiarella, M.D., Division of Allergic Diseases, ces hyperventilation and results in a decreased (partial
Mayo Clinic, 200 First St. SW, Rochester, MN 55905
pressure of carbon dioxide; PaCO2) with transient respi-
E-mail address: [email protected]
Copyright © 2023, OceanSide Publications, Inc., U.S.A. ratory alkalosis.12 Due to these physiologic changes,
60%–70% of pregnant women can experience dyspnea

24 January 2023, Vol. 44, No. 1

Table 1 Summary of physiologic changes during pregnancy
System Comment
Cardiovascular Cardiac output increases while systemic vascular resistance and blood pressure decrease; red
blood cells and plasma volume increase
Respiratory Progesterone induces hyperventilation with subsequent changes in PaCO2 and contributes to
the physiologic dyspnea of pregnancy; as the gravid uterus enlarges and diaphragm dis-
placement occurs, functional residual capacity decreases by 20%*: FVC, FEV1, and PEF do
not change, which makes spirometry variables used for asthma diagnosis comparable
between pregnant and nonpregnant patients
Immune Implantation is characterized by a predominant proinflammatory chemokine release with a
subsequent anti-inflammatory environment to ensure fetal development and tolerance;
immune system changes during pregnancy are partly explained by hormonal changes;
pregnant women with asthma have higher levels of proinflammatory chemokines and
higher oxidative stress throughout the pregnancy#
PaCO2 = ; FVC = forced vital capacity; FEV1, = forced expiratory volume in the first second of expiration; PEF = peak expira-
tory flow; PaCO2 = partial pressure of carbon dioxide.
*From Ref. 12.
#Adapted from Ref. 92.

during the first and second trimesters.12–14 Importantly, killer cell activity, facilitating an anti-inflammatory
compared with pregnant women who are not asthmatic, environment.26 In pregnant women with asthma, an
lung function changes are more pronounced in pregnant abnormally increased Th2 response is present.26 Notably,
women with asthma. an observational study in pregnant women found higher
The immune system also changes during pregnancy. levels of interleukin (IL) 4, IL-6, and IFN-g .27 In addition,
For instance, there is a predominant T-helper type 1 a statistically significant negative correlation has been
(Th1) response in the first trimester with a subsequent reported between the levels of IL-4 and IFN-g and mater-
shift to a T-helper type 2 (Th2) response in the second nal peak expiratory flow among pregnant women with
and third trimesters.15,16 The recruitment of specialized asthma.28 Furthermore, asthma during pregnancy
immune cells occurs within the decidua on implanta- increases the circulating level of proinflammatory
tion, which mostly contains macrophages, natural C5a, which is accompanied by impaired lung func-
killer cells, regulatory T cells (Treg), and dendritic tion and partly counteracted by the gestation-specific
cells, which creates a proinflammatory environment elevation of regulatory complement factor H level.29
that favors trophoblastic invasion.17,18 After the first Exhaled breath condensate pH is higher in healthy
weeks of gestation, there are changes in B-cell popula- pregnant women compared with their counterparts
tions, including a decrease in total B-cell numbers.18,19 with asthma, which suggests oxidative inflammation
Among the most significant changes, an increasing at play in pregnant women with asthma.30 Moreover,
regulatory B cell population promotes immune toler- studies have also shown an increase in exhaled breath
ance to avoid fetal rejection.20 Furthermore, there is condensate pH during asthma exacerbations.31 The
evidence that Tregs also promote anti-inflammatory physiologic changes during pregnancy are summar-
conditions during the second trimester.21 Interestingly, ized in Table 1.
other studies22–44 have shown multiple abnormalities
in immune cell subgroups of women with asthma dur- DIAGNOSIS
ing pregnancy. There is an increased number of B cells, Most pregnant women with asthma already have an
memory cells, plasmablasts,22 monocytes, and neutro- established diagnosis before gestation. For those who
phils compared with women who are not asthmatic.23 present with respiratory symptoms during pregnancy
In addition, the pregnancy-induced increase in Tregs is and without a previous diagnosis of asthma, multiple
decreased in asthmatic pregnancy, which may interfere conditions need to be considered. Importantly, 60% of
with fetal development and tolerance.24 pregnant women report shortness of breath due to the
Hormonal changes during pregnancy also influence previously described changes in the pulmonary sys-
the cytokine milieu.25 In particular, the gradual tem.32 However, shortness of breath that impairs func-
increase of estrogen and progesterone at the end of tionality and the association with other symptoms
the first trimester reduces tumor necrosis factor a pro- such as chest pain, cough, or wheezing warrant further
duction, interferon (IFN) g expression, and natural workup. Medical conditions to consider include upper

Allergy and Asthma Proceedings 25

Table 2 Asthma severity classification in pregnant women*
Daytime Nighttime Impaired FEV1 or PEF
Severity Symptoms Symptoms Functionality PEF, % Variability, %
Severe persistent Constantly >4 times/week Very limited <60 >30
Moderate persistent Frequently >1 time/week Limited 60–80 >30
Mild persistent >2 times/week >2 times/month Minor limitation >80 20–30
but not daily
Mild intermittent <2 days/week <2 times/month None >80 <30
FEV1, = Forced expiratory volume in the first second of expiration; PEF = peak expiratory flow.
*Adapted from Ref. 67.

respiratory infections, gastroesophageal reflux disease, (QualityMetric Incorporated, Johnston), have been used
pulmonary embolism, pulmonary edema, and asthma.33 and validated to assess asthma control in pregnant
A clinical presentation typical of asthma increases women.42,43
the probability of this condition but is not confirma- Other tools to assist asthma control evaluation during
tory. Importantly, forced vital capacity and forced ex- follow-up of pregnant patients are being studied. For
piratory volume in the first second do not change instance, fractional exhaled nitric oxide (FeNO), was
during pregnancy.10 A confirmed parameter of expira- evaluated in a prospective study44 in which 111 women
tory flow limitation should be met with lung function were randomly assigned to the FeNO group. An exacer-
testing and a bronchodilator test, as referenced in The bation rate was lower in the FeNO group than in the
Working Group on Asthma and Pregnancy control group, with a number needed to treat of six. In
Guidelines.34 In addition, asthma severity is classi- the FeNO group, the quality of life was improved.44,45
fied according to the parameters defined by the As with nonpregnant adults with asthma, further stud-
National Asthma Education and Prevention Program ies are needed to evaluate FeNO-guided treatment.
Working Group on Asthma and Pregnancy as mild,
moderate, moderate with additional therapy, and severe MATERNAL AND FETAL OUTCOMES
(Table 2). This classification considers daytime and Asthma has been associated with a wide variety of
nighttime symptoms plus spirometry values and impli- complications and adverse outcomes for mothers in all
cations for treatment options.35,36 phases of gestation and among neonates, with a grow-
ing prevalence in recent years.46 As stated by Kwon et
FOLLOW-UP al.,47 higher numbers of pregnant women with asthma
Asthma’s course during pregnancy is highly vari- are driven by an increasing prevalence of asthma
able. Retrospective and prospective studies have among younger pregnant women, likely as a conse-
shown that asthma worsens in a third of patients, quence of lifestyle and urbanization changes.48,49 Some
improves in a fourth of patients, and remains investigators postulate that complications among preg-
unchanged in a third of them, with similar disease nant women are increasing due to increased obesity,
courses in subsequent pregnancies.37 In addition, consumption of tobacco products, and a higher preva-
asthma severity during pregnancy is similar to the se- lence of psychosocial issues.50 Some complications
verity observed during the prepregnancy state when reported by observational studies include spontaneous
these patients continued to use their medications.38 abortion, antepartum and postpartum hemorrhage,
Determinants of low-risk asthma exacerbation are clin- placental abruption, gestational diabetes, cesarean sec-
ically stable asthma, no history of exacerbations, and tion, placenta previa, premature rupture of mem-
no necessity of treatment with controller medication branes, preterm birth, a higher risk of a breech
because of mild disease.39 presentation, pulmonary embolism, and maternal in-
Evaluation of asthma control during pregnancy is crit- tensive care unit admission.51–56
ical, and it should be assessed by spirometry and vali- Furthermore, it seems that asthma severity influen-
dated questionnaires in prenatal visits.40 As described in ces the risk of complications because adverse outcomes
the Global Initiative for Asthma (GINA) recommenda- are more prevalent in pregnant women with moder-
tions,41 an assessment of asthma symptom control could ate-to-severe asthma.52 Pregnant women with asthma
be made by questioning the frequency of asthma symp- are also at an increased risk of experiencing transient
toms, the necessity of short-acting inhaled therapy, and hypertension of pregnancy, preeclampsia, or eclampsia.57
the time of appearance of such symptoms. In addition, Notably, obesity and weight gain during pregnancy
numerical questionnaires, e.g., the Asthma Control Test have also been associated with worse outcomes in

26 January 2023, Vol. 44, No. 1

 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 percep-
tions of disease course to ensure proper adherence.66
Pregnant women with asthma and with associated
comorbidities, including atopy, rhinitis, and gastro-
esophageal reflux disease, require proper management
to avoid poor asthma control (Table 3). For instance, at-
opy treatment needs lifestyle modifications and avoid-
ance 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 contra-
indicated during pregnancy due to concerns of
anaphylaxis.69
Multiple studies exhibited the association of appro-
priate asthma control and perception of the disease
with multidisciplinary team involvement in the care of
pregnant women with asthma.70 Interestingly, antena-
tal asthma management services reduce the risk of
exacerbations, persistent uncontrolled asthma, and
loss of disease control.58,71,72 In this regard, a random-
ized 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
Figure 1. Comorbidities and socioeconomical factors to consider study demonstrated a decrease in the rate of asthma
when managing women with asthma during pregnancy. exacerbations and improvement in disease control
among pregnant women.73
pregnant patients with asthma, and this relationship As mentioned in the GINA recommendations,41
asthma management should consider symptom control
seems to increase in a dose-dependent matter.58
and risk reduction when prescribing medication. There
Maternal asthma is also associated with an increased
is evidence of the importance of controlling asthma
risk of multiple diseases in the offspring, including
exacerbations in pregnant women to avoid substantial
infectious, respiratory, cutaneous, and hematologic
morbidity, mortality, and adverse fetal outcomes.74,75
illnesses,59 and childhood asthma.60 A higher rate of
As such, continuing inhaled therapy during pregnancy
congenital abnormalities and being small for gesta-
outweighs the risks of potential medication adverse
tional age have also been noted.46 In contrast,
effects.76,77 Medications for pregnant women with
another study found no significant association
asthma include inhaled corticosteroids, leukotriene
between maternal asthma and birth weight, Apgar
receptor antagonists, long-acting b 2-agonists, short-
scores, or respiratory distress syndrome.61
acting b 2-agonists, inhaled muscarinic antagonists,
and, most recently, biologics.41 The therapeutic
TREATMENT options according to asthma severity are summarized
Management of asthma in pregnant patients includes in Table 4.41
education about the disease, inhaler technique, the im- Medication nonadherence is a critical problem when
portance of adherence independent of risk classification, managing pregnant women with asthma. In a popula-
and management of other associated comorbidities.62 tion-based control study78 that describes the use of
It is essential to identify potential roadblocks to asthma medications during pregnancy, the investiga-
adequate asthma management in pregnant women tors described that 85% of women with asthma used
(Fig. 1). A retrospective cohort study of 115,169 albuterol, 46% used fluticasone, and 15% used monte-
pregnant women with asthma recognized a tend- lukast. Importantly, 70% of women who used inha-
ency of these patients to decrease their asthma ther- led bronchodilators during the preconception period
apy during gestation with a subsequent increase in continued their use amid gestation,78 with other medica-
the rate of exacerbations.63 Furthermore, poor tions being more frequently discontinued.79 Limitations

Allergy and Asthma Proceedings 27

Table 3 Comorbidities that can exacerbate asthma during pregnancy
Comorbidity and References Comment and References
90,93,94
GERD Prevalence was high in pregnant women in general93; increased relaxation of
the lower esophageal sphincter caused by progesterone during pregnancy
exacerbates GERD and, subsequently, may increase asthma severity90
95
Respiratory viral infection Reduced antiviral interferons and increased levels of inflammatory cytokines,
e.g., IL-17, during pregnancy increase susceptibility, morbidity, and mortal-
ity96,97; also, viral infections are the most common cause of asthma exacerba-
tions in pregnancy98
46,99
Diabetes mellitus Poorly controlled diabetes is associated with increased asthma exacerbations100;
also, associated with wheezing in the child of mother with diabetes101–103
46
Chronic arterial hypertension Asthma increases the likelihood of hypertensive disorders of pregnancy,
including chronic arterial hypertension, which, in turn, increases the proba-
bility of wheezing in offspring104
105
Obstructive sleep apnea Increases the risk of severe asthma106
107
Obesity Obesity during pregnancy increases the likelihood of asthma in offspring108,109
46
Thyroid disease Maternal hypothyroidism increases the probability of childhood wheezing110
46
Smoking Asthma severity is correlated with smoking111; maternal cigarette consumption
is associated with asthma in the offspring112
113
Alcohol consumption Increased alcohol consumption is associated with asthma severity and
exacerbations113
114
Illicit drug use Associated with socioeconomic and race disparities114
115
Allergic rhinitis Correlation between asthma and allergy control with severe asthma has been
observed115,116
117–119
Rhinitis during pregnancy Increased cholinergic activity caused by estrogen during pregnancy results in
nasal mucosa edema, rhinorrhea, and congestion117;arises in ;20% of
pregnancies120
121
Fertility Thought to be secondary to increased inflammation within the decidua, which
impairs implantation122; also associated with a prolonged time to
conception123
Psychiatric comorbidities, such as Associated with increased asthma exacerbations125; asthma in pregnancy is cor-
depression and anxiety related with postpartum depression126
124
disorders
GERD = Gastroesophageal reflux disease; IL = interleukin.

for adequate asthma management include medication of omalizumab in pregnant women treated preconcep-
safety concerns during pregnancy because women tionally and not initiating it during pregnancy.82
perceive a deleterious effect on the fetus as a reason Animal studies and case reports of patients with
to discontinue therapy. Importantly, evidence from asthma who received anti–IL-5 biologics and dupilu-
multiple observational studies has not shown a stat- mab during pregnancy suggest that these biologics
istically significant correlation between inhaled ther- have a good safety profile.83–89 Further prospective
apy and congenital heart defects,78 and cleft lip, studies are warranted to investigate the effects of
stillbirth, neonatal hospitalization, respiratory dis- asthma biologics during pregnancy.
tress syndrome, and neonatal sepsis.80 Notably, Experimental and epidemiologic evidence has
inhaled corticosteroids do not seem to affect fetal ad- revealed increased reactive oxygen species produc-
renal function.81 tion and inflammation during asthma in preg-
It is also important to note that there is a surge in nancy. Introducing dietary antioxidants might
novel therapies for asthma, including biologics, e.g., decrease asthma severity, 90 as demonstrated in
omalizumab.70 Notably, a prospective cohort study some randomized controlled trials that used lycopene
did not demonstrate an increased risk of congeni- and b -carotene as supplements.91,92 However, interven-
tal abnormalities in pregnant women treated with tional studies in pregnant women with asthma are
omalizumab.70 Nonetheless, because evidence is lim- needed to fully elucidate the benefits of antioxidants in
ited, current guidelines recommend continuing the use this population.62

28 January 2023, Vol. 44, No. 1

Table 4 Medications for the management of asthma during pregnancy
Medication Comment and References
ICS A pillar of asthma management as a controller and reliever when combined
with formoterol in mild intermittent asthma; combined with another LABA
in mild persistent, moderate persistent, and severe persistent asthma, with
dose increments, depending on severity; overall, evidence has shown safety
with the use of ICS 63,76,78,113,127–129; evidence has not shown an increased
risk of congenital heart defects,76 preterm birth, low birth weight,130 or other
congenital malformations129
LABA Used as a controller in combination with ICS in patients with moderate persis-
tent and severe persistent asthma; evidence in animal experiments and obser-
vational studies in humans have shown safety with formoterol and
salmeterol131
LRA Used as a second-line controller in mild persistent asthma and in combination
with ICS in moderate persistent asthma; limited evidence has shown safety
with montelukast and zafirlukast62,68,127,132–134
Anti-IgE Omalizumab is used as an add-on in moderate-to-severe persistent asthma, de-
spite appropriate use of ICS; there is limited evidence of safety with omalizu-
mab, with a prospective observational exposure registry study of 250
pregnant women with asthma who used omalizumab, with no evidence of
congenital anomalies80; nonetheless, omalizumab should not be initiated dur-
ing pregnancy135
Anti–IL-5 Anti–IL-5 medications are indicated as an add-on maintenance therapy in per-
sons with severe eosinophilic asthma,136 and most cross the placenta during
the third trimester137; pregnant monkeys exposed to benralizumab did not
encounter fetal malformations or limited neonatal growth137; fetal harm was
not evidenced in animal studies that used mepolizumab; there are few case
reports of pregnant women exposed to mepolizumab without fetal outcomes
assessed138,139; no evidence of fetal malformations was shown in studies of
animals while they were exposed to reslizumab; no human studies exist140
Anti–IL-4 and -13 Dupilumab is indicated as add-on therapy for severe eosinophilic asthma or
oral corticosteroid–dependent asthma141; no evidence of fetal adverse out-
comes was noted in pregnant monkeys exposed to dupilumab; no human
studies128,140
SABA Used as a second-line inhaler for symptom relief; limited observational studies
showed safety with albuterol and formoterol131; formoterol is used as a
symptom reliever in combination with an ICS41
Systemic corticosteroids Used in acute asthma exacerbations and severe asthma; despite concerns of con-
genital anomalies, such as cleft palate,142 preterm birth, and low birth
weight, 130,143–145 the benefits of using oral corticosteroids when indicated
outweigh these risks; other obstetric complications related to oral corticoste-
roids include preeclampsia146
Inhaled muscarinic antagonists Used as add-on in acute exacerbations and moderate-to-severe uncontrolled
asthma, despite LABA-ICS therapy; high doses of tiotropium bromide may
induce fetal toxicity in animal studies; no evidence in humans exists128; evi-
dence when using ipratropium bromide indicates no fetal harm in animal
studies at high doses147
ICS = Inhaled corticosteroid; LABA = long-acting b -2 agonist; LRA = leukotriene receptor antagonist; IgE = immunoglobu-
lin E; IL = interleukin; SABA = short-acting b 2-agonists.

Allergy and Asthma Proceedings 29

MANAGEMENT OF ACUTE EXACERBATIONS medications. This is particularly important given the
Fifty percent of asthma exacerbations during preg- advent of novel biologics for the treatment of asthma.
nancy occur before 20 weeks of gestation 93 and are
associated with adverse obstetric outcomes,94 includ- REFERENCES
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