U se o f A sth m a Med i cat io n

During Gestation and Risk of

Specific Congenital Anomalies
Ruth P. Cusack, MBBcha, Christiane E. Whetstone, BSc
b
,
Gail M. Gauvreau, PhD, Professorc,*

KEYWORDS
 Asthma medication  Congenital anomaly  Pregnancy

KEY POINTS
 Inhaled corticosteroids and long-acting b-agonists are safe in pregnancy.
 Low priority should be placed on stepping down treatment until after delivery in a well-
controlled patient.
 Good education before and during pregnancy is important to ensure compliance to
asthma medication.
 More data on the use of biological therapies for asthma in pregnancy is needed.

INTRODUCTION

Asthma is one of the most common medical conditions to affect pregnancy with a
prevalence of between 5% and 13% of pregnancies,1–3 with prevalence increasing
in recent years in the United States.4,5 Poorly controlled maternal asthma during preg-
nancy is common, affecting up to 28% of pregnancies,1 and can affect maternal health
(preeclampsia) and neonatal outcomes (congenital anomalies, preterm delivery,
increased perinatal mortality, low birth weight).5,6 These complications can potentially
be reduced with appropriate management of asthma and its exacerbations during
pregnancy.7,8
The treatment of asthma during pregnancy follows the same principles as asthma
management in the general adult population with asthma medications divided into
rescue therapy and maintenance therapy.9,10 Using a stepwise approach to asthma
therapy ensures the lowest amount of medication necessary is used to control the

a
Department of Medicine, McMaster University, HSC 3U31 F, 1200 Main Street West, Hamilton,
Ontario L8N 3Z5, Canada; b Department of Medicine, McMaster University, HSC 3U20, 1200
Main Street West, Hamilton, Ontario L8N 3Z5, Canada; c Department of Medicine, McMaster
University, HSC 3U31E, 1200 Main Street W, Hamilton, Ontario L8N 3Z5, Canada
* Corresponding author.
E-mail address: [email protected]

Immunol Allergy Clin N Am 43 (2023) 169–185

https://doi.org/10.1016/j.iac.2022.07.007 immunology.theclinics.com
0889-8561/23/ª 2022 Elsevier Inc. All rights reserved.
170 Cusack et al

patient’s symptoms, with increasing number and dosage of medications with

increasing asthma severity. However, one of the biggest challenges in managing
asthma during pregnancy is medication adherence, and despite clear guidelines,
many women remain concerned about a potential negative effect of treatment on their
unborn child. A cross-sectional study by Al Ghobain and colleagues11 investigated the
views of pregnant women with asthma and found that 46.8% of pregnant asthmatic
women had stopped (or expressed a desire to stop) their asthma medications during
pregnancy, and 48% believed asthma medications would harm them and their babies.
Powell and colleagues12 previously found pregnant women with asthma overesti-
mated the teratogenic risk of asthma medications with 42% perceiving a teratogenic
risk with oral corticosteroids (OCSs), 12% a risk with inhaled corticosteroids (ICSs),
and 5% a risk with short-acting b-agonists (SABAs). Despite women’s concerns
regarding the risk of asthma medications during pregnancy, the benefit of asthma ed-
ucation cannot be underestimated with only 40% of women more likely to continue
their asthma medication during pregnancy if their obstetrician alone recommended
it.13 There is also evidence of suboptimal management of asthma within primary
care. An Australian anonymous mail survey of 174 general practitioners found
25.8% of respondents would stop or decrease patients’ ICS dose during pregnancy,
even if asthma was well controlled on current therapy, and 12.1% of respondents indi-
cated they did not know how to manage a deterioration of asthma during pregnancy.14
The overall risk of congenital abnormalities with maternal asthma is slightly
increased; however, there is a lack of consensus concerning the effects of asthma
medications versus the disease itself on the development of congenital anomalies
because confounding factors can contribute to some of these associations.15–17
Maternal asthma exacerbations during the first trimester of pregnancy significantly in-
crease the risk of congenital abnormalities (adjusted odds ratio [AOR] 5 1.48; 95%
confidence interval [CI], 1.04–2.09), because this is a critical period of embryogenesis
when congenital anomalies happen.18 Treatments that maintain asthma control during
pregnancy are favorable to optimize both maternal and fetal health, and the risk of
poor asthma control greatly outweighs the risk of treatment side effects, particularly
with regard to congenital anomalies.

Congenital Anomalies: Definition, Detection, and Risk Factors

Congenital anomalies may be detected prenatally, at birth, or later in infancy such as
hearing or visual anomalies. In recent decades there have been major improvements in
congenital anomalies diagnosis because prenatal ultrasonography has become a
standard part of prenatal care, with prenatal diagnosis of structural malformations
of most organ systems detectable during pregnancy.19
Different congenital anomalies and patterns are due to a teratogenic insult at partic-
ular gestational stages (Fig. 1). After the egg is fertilized and before implantation, the
result of a teratogenic insult is an all or nothing effect. The first 8 weeks of pregnancy,
often before the first identification of pregnancy, is termed blastogenesis (weeks 0–4)
and organogenesis (weeks 4–8), when the embryo develops into tissues and organs.
Insults during blastogenesis can result in severe, often lethal anomalies that involve
several organ systems. Insults during organogenesis tend to involve single organ
structures; for example, weeks 3 to 5 are critical for central nervous system develop-
ment, and weeks 7 to 9 for urogenital development. During the fetal period (after
8 weeks gestation), harmful influences may affect fetal growth and function (eg, hear-
ing loss, cognitive impairment, lung immaturity). Therefore, timing of exposure of a
particular event or insult, duration and frequency of exposure, can result in very
different outcomes.
 Use of Asthma Medication During Gestation 171

Fig. 1. Risk of teratogenic outcomes with asthma treatment. LAMA, long-acting muscarinic
agonist; LT, leukotriene; mAb, monoclonal antibody; MX, methylxanthine; SAMA, short-
acting muscarinic antagonist. aHigh-dose ICS (>1000 mg/d beclomethasone equivalent) in
the first trimester could be associated with a small increased risk of congenital anomaly.

The risk factors for developing anomalies can be classified as modifiable (environ-
mental, smoking, obesity, diabetes, medications, folic acid deficiency) and nonmodi-
fiable (genetic), although in most cases the cause remains unknown. A genetic
predisposition to specific teratogens has been studied extensively. Maternal and fetal
genetic variants have been associated with an embryo’s susceptibility to develop fetal
alcohol syndrome.20 Cigarette smoke exposure is a risk factor for the development of
orofacial clefts and gastroschisis in the fetus; however, the risk is increased even
further if the fetus carries specific, rare genotypes.21,22 Specific medications are
172 Cusack et al

known teratogens. For example, methotrexate due to its role as a folic acid antagonist
leads to microcephaly, cardiac effects, and limb anomalies23; lithium use in early preg-
nancy is associated with cardiac anomalies24; and phenytoin causes major malforma-
tions including facial clefts and cardiac disease.25 Although it is preferable that all
pregnant women refrain from taking any medications during pregnancy, this is not al-
ways possible, and therefore, primary prevention within the whole population by con-
trolling environmental risk factors and ensuring optimum preconceptual care is a
crucial health care priority.

Safety of Asthma Medications During Pregnancy

Pregnant women are generally excluded from clinical trials due to a lack of safety in-
formation on most medications in pregnancy; therefore knowledge regarding safety
for the fetus is usually presented from large population studies (Table 1). Thus, exist-
ing information is usually limited, and more studies are required due to lack of informa-
tion or potential confounders. Unfortunately animal studies are not always predictive
of teratogenic effect in humans,26 as observed with thalidomide, which was approved
for use outside the United States for pregnant women suffering from morning sickness
in the late 1950s and the early 1960s but was found to result in limb congenital anom-
alies despite animal studies finding only occasional teratogenic events.27
The treatment of asthma during pregnancy follows the same principles as asthma
management in nonpregnant patients. Asthma medications are divided into mainte-
nance and rescue therapy. Maintenance therapies are used long term to prevent
asthma symptoms and exacerbations and include ICSs, long-acting b-agonists
(LABA), antileukotrienes, anticholinergic agents, theophylline, and more recently bio-
logical therapies, whereas rescue therapies, primarily rapid-onset bronchodilators
such as SABAs, provide immediate relief of symptoms. Although there is a general
concern about any medication use in pregnancy, an important role for a clinician is
to stress the importance of maintaining good control of asthma and medication adher-
ence while reassuring a pregnant woman of the safety of asthma medications during
pregnancy. Although treatment adjustments can be made during pregnancy, the
Global Initiative for Asthma (GINA) recommends that “given the evidence in pregnancy
and infancy for adverse outcomes from exacerbations during pregnancy, including
due to a lack of ICS or poor adherence, and evidence for safety of usual doses of
ICS and LABA, a low priority should be placed on stepping down treatment (however
guided) until after delivery, and ICS should not be stopped in preparation for preg-
nancy or during pregnancy.”9

Inhaled Corticosteroids
ICSs have been the cornerstone of asthma therapy for more than 40 years and are rec-
ommended as a first-line therapy for asthma in both adolescents and adults, recently
replacing SABAs as the first-line therapy for mild asthma.9 However, ICS adherence
during pregnancy is poor with 39% of pregnant women reporting nonadherence28
despite studies showing that ICS does not increase risk of congenital anomalies asso-
ciated with its use,29 ICS reduces asthma exacerbations in pregnancy,30 and cessa-
tion of ICS increases the risk of developing exacerbations, which are a risk factor
for congenital anomalies rather than asthma itself (AOR 5 1.21; 95% CI, 1.05–1.39).31
Concerns raised about a potential association of congenital anomalies and moder-
ate- to high-dose ICSs have been examined. A previous literature review32 summari-
zing the risk of congenital malformations with the use of ICSs in pregnancy found that
in 15 separate studies29,33–46 comparing women with asthma using any ICS versus
women with asthma not using ICS the adjusted relative risk ranged from 0.4 to 1.1.
Table 1
Summary data for asthma medications and risk of congenital anomalies

Drug Category Preferred Drugs Human Data Considerations

Inhaled corticosteroids Budesonide (more published data) At low and moderate doses no If well controlled on an ICS before
Beclomethasone (reassuring data) increased risk of congenital pregnancy this may be continued
anomalies. One study showed because changing drug may
at >1000 mg/d beclomethasone threaten asthma control
equivalent in the first trimester
there was a small increased risk of
congenital anomaly47
Inhaled SABAs Salbutamol/albuterol (more Recommended as safe in pregnancy. Goal is to minimize SABA use using
published data) Large population studies have ICSs to ensure adequate control
found no association between
b-agonists and congenital
anomalies51
Inhaled LABAs Salmeterol Similar safety profile to SABAs LABA monotherapy should not be

Use of Asthma Medication During Gestation

Formoterol used
Indacaterol Animal studies for once-daily LABAs These agents are not first choice in
Vilanterol are reassuring; however, no human pregnancy unless a once-daily fixed
data are available combination regime is required to
ensure adherence
Combination therapy Low-dose ICS-formoterol can be used The use of ICS-LABA combination did Limited studies, however, probably
as maintenance and reliever not result in a significant increased safe in pregnancy with no increased
therapy risk of congenital anomalies congenital anomaly risk
compared with high-dose ICS alone
during the first trimester56
Oral corticosteroids Prednisone (more published data) Conflicting data; however, recent Major benefit outweighs the risk in
studies suggest no increased risk of severe asthma
congenital anomalies58,59

(continued on next page)

173
 174
Cusack et al
Table 1
(continued )
Drug Category Preferred Drugs Human Data Considerations
Antileukotrienes Montelukast (more published data) A cohort study of 180 montelukast- Zileuton not recommended in
exposed pregnancies found pregnancy due to fetal
montelukast did not increase the abnormalities in animal studies.61
risk of major congenital Montelukast probably safe as an
anomalies63 add-on therapy in uncontrolled
asthma
Anticholinergics Ipratropium Nebulized ipratropium recommended No published data for tiotropium in
for acute, severe asthma not pregnancy
responding to b-agonists alone
Theophylline N/A No increased risk of congenital No evidence of teratogenic effects.
anomalies compared with inhaled Blood levels should be monitored
beclomethasone; however,
increased risk of discontinuation
due to side effects38
Monoclonal antibody therapies Omalizumab No increased risk of congenital Probably safe in pregnancy; however,
anomalies with omalizumab69 larger studies are needed
Mepolizumab No published human data Pregnancy registry ongoing
Reslizumab No published human data Pregnancy registry ongoing
Benralizumab No published human data Pregnancy registry ongoing
Dupilumab A review of 23 pregnancies in study EMA states dupilumab should only be
patients found no increased risk of used during pregnancy if the
congenital anomalies; however, low potential benefits outweigh the
numbers of pregnancies, therefore risks.81 Pregnancy registry ongoing
more data needed78
Tezepelumab No published human data No pregnancy registry

Abbreviations: EMA, European Medicines Agency; LABA, long-acting b-agonist; N/A, not applicable.
 Use of Asthma Medication During Gestation 175

Bakhireva and colleagues35 were the only investigators to report a significantly

increased risk of congenital anomalies associated with ICS use when they compared
438 pregnant women using ICSs during pregnancy with nonasthmatic control preg-
nant women (4.1% vs 0.3% presence of major anomalies, respectively, P 5 <0.05).
Blais and colleagues47 studied 13,280 pregnancies in women with asthma and found
1633 congenital anomalies, the most frequent being cardiac and musculoskeletal.
High daily ICS use (>1000 mg/d beclomethasone equivalent) during the first trimester
was associated with a significant risk of congenital anomalies (AOR 5 1.63; 95% CI,
1.02–2.60), compared with women taking low- or medium-dose ICSs. These results
must be interpreted with caution, however, because the number of women taking
high-dose ICSs was small (n 5 154, 1.1%), and the results were based on medication
claims and not actual usage. Furthermore, the investigators could not out rule asthma
severity, age, or socioeconomic group confounding the results. However, with respect
to the first trimester, women who abstained from ICS use had a higher risk of congen-
ital anomalies in their baby compared with women who used low- or moderate-dose
ICS, supporting the belief that uncontrolled maternal asthma rather than ICS is asso-
ciated with congenital anomalies. In addition, the ICS budesonide has been studied
extensively in pregnancy with a large body of safety data showing no increased risk
of congenital anomalies or stillbirths34,48,49 and is considered first-line ICS if
commencing therapy during pregnancy; however, if a patient is well controlled on
an ICS before pregnancy this may be continued because changing formulations
may threaten asthma control.

b-Agonists
SABAs provide symptom relief by rapidly reversing the effects of bronchoconstriction
in asthma and are now recommended as an add-on therapy for patients taking ICSs.9
LABAs are the second most widely used controller medication in asthma and
compared with SABAs they provide more prolonged bronchodilation, with a greater
reduction in symptoms, increased lung function, and reduced need for SABAs. SABAs
are recommended as safe in pregnancy.10 LABAs when used alone have previously
been associated with increased asthma-related mortality in general,50 and therefore
they are only recommended as an add-on controller therapy in fixed-dose combina-
tion with ICSs to treat moderate to severe asthma.
A study examining more than 76,000 registrations of congenital abnormalities raised
concerns finding an association between inhaled b-agonist exposure during the first
trimester and congenital anomalies including cleft palate and gastroschisis.17 Howev-
er, a larger population-based cohort study of more than 519,242 infants, including
19,513 mothers with asthma medication exposure, found no significant association
between inhaled b-agonists and cleft palate (AOR 5 1.05; 95% CI: 0.44–2.51) or gas-
troschisis (AOR 5 1.08; 95% CI, 0.37–3.15),51 suggesting no association between
b-agonists and congenital anomalies. A systematic review of 21 published studies
that examined b-agonist use and congenital anomalies52 found only 1 study that re-
ported a significant risk of congenital anomalies with LABA, whereas 4 studies found
a significantly higher risk of congenital anomalies with SABA and 1 reported a signif-
icantly lower risk of congenital anomalies with SABA. The investigators state, however,
these results must be interpreted with caution because all studies except 2 used non-
asthmatic women as the reference group, which could have confounded the underly-
ing asthma disease and the effect of medication, and further studies are required.
Inhaled salbutamol is considered the first-line SABA therapy for pregnant women
because it has been studied most extensively.29 There is no preferred LABA therapy
in pregnancy, and a previous study showed no difference in perinatal complications
176 Cusack et al

between salmeterol or formoterol exposure; however, congenital anomalies were not

specifically examined.53 Therefore, the goal of asthma management in pregnant
women is to minimize the use of SABAs using ICSs, and if required, adding a LABA,
to ensure adequate control and prevent severe exacerbations known to increase
the risk of congenital anomalies. Ultra-LABAs (eg, indacaterol and vilanterol) are newer
LABAs used in a once-daily fixed combination with ICSs. Although animal studies for
ultra-LABAs suggest low risk of congenital anomalies, no human data are available.
Thus, these agents are not our first choice in pregnancy unless a once-daily fixed com-
bination regime is required to ensure adherence.

Combination Therapy
Asthma management for adolescents and adults is based on a stepwise approach.
When asthma cannot be controlled with low-dose ICS alone, guidelines suggest add-
ing LABA in a fixed-dose inhaler or increasing the ICS dose to the medium range.9 As
needed low-dose ICS-formoterol is now recommended as the first-line therapy for
mild asthma instead of SABA9 because it has been associated with reduced asthma
exacerbations and improved peak flows and forced expiratory volume in the first sec-
ond of expiration compared with as-needed SABA.54 ICS-formoterol combination can
also be used as a maintenance and reliever therapy and is effective at reducing exac-
erbation risk, and results in a simplified approach to asthma management.55
Pregnant women were excluded from clinical trials assessing the safety of ICS-
formoterol combination therapy as needed and as a maintenance and reliever therapy,
limiting our knowledge of safety in pregnancy. Physician’s and patient’s perception of
medication risk of teratogenicity due to lack of clinical trial evidence for these agents
may result in them changing treatment regimen during pregnancy. A Canadian retro-
spective cohort study of 1302 asthmatic pregnant women assessed the risk of
congenital malformations in women using ICS-LABA combination versus high-dose
ICS alone in the first trimester.56 The use of ICS-LABA combination had a similar
risk of congenital anomalies compared with high-dose ICS alone during the first
trimester (AOR 5 1.0; 95% CI, 0.6–1.7) in moderate to severe asthma. These results
are reassuring and suggest that ICS-LABA combination therapy is safe in pregnancy
with no increased congenital anomaly risk, and should provide reassurance to both
women and physicians to continue their asthma combination medication during
pregnancy.

Oral Corticosteroids
OCSs may be required for the treatment of acute exacerbations or used at low dose
for management of persistent severe asthma. There are more data regarding the
safety of prednisone for pregnant women because it has been studied more
extensively.
There are conflicting data regarding the risk of congenital anomalies and OCS in
pregnancy. Park-Wyllie and colleagues57 performed a meta-analysis of 10 studies
showing an increased risk of orofacial anomalies when OCS is used during the first
trimester only (odds ratio [OR] 5 3.35; 95% CI, 1.97–5.69). These results must be inter-
preted with caution because 7 studies included women with various underlying con-
ditions requiring OCS use, whereas three studies did not describe the mother’s
indication for OCS. And this could have resulted in confounding, therefore further
studies are required assessing the effect of OCS in asthma alone during pregnancy.
Reassuringly data from the National Birth Defects Prevention Study of 1304 congenital
anomaly births in women who reported any asthma medication use from 1997 to 2011
found no increased risk of cleft lip and prednisone use.58,59 As a previous study found
 Use of Asthma Medication During Gestation 177

an association between first-trimester severe asthma exacerbation requiring hospital-

ization and congenital anomalies when compared with women with asthma who did
not require a visit to the emergency department or hospitalization (OR 5 1.64; 95%
CI, 1.02–2.64),60 the benefit of OCSs in the prevention of severe asthma exacerbations
outweighs the potential risk of congenital anomalies associated with their use.

Antileukotrienes
Montelukast and zafirlukast are selective leukotriene receptor antagonists (LTRAs)
indicated as maintenance controller therapies for asthma. Although data for the use
of both agents are limited in pregnancy, montelukast is the first-line LTRA therapy dur-
ing pregnancy because it has been studied most extensively. Zileuton is a leukotriene
synthesis inhibitor that is not recommended in pregnancy due to fetal abnormalities in
animal studies61 with no evaluation of safety in human pregnancy.
Montelukast is indicated as an add-on therapy for asthma; however, a Danish
cross-sectional observational study through a prescription-based database attemp-
ted to realize the risk of congenital abnormalities associated with montelukast in preg-
nant women when used as a single agent (n 5 401) compared with its use
simultaneously with other asthma medications (n 5 426) during the first trimester of
pregnancy.62 Rates of major congenital anomalies were not different in the
montelukast-only group (AOR 5 1.4; 95% CI, 0.9–2.3) when compared with montelu-
kast simultaneously with other asthma medications (AOR 5 1.0; 95% CI, 0.6–1.8) or
when compared with other asthma medications alone (AOR 5 1.1; 95% CI, 1.0–
1.2). This study did have several limitations because the number of congenital anom-
alies was low (16 in the montelukast alone group) reducing the statistical power. The
study did not have sufficient power to look for associations with specific anomalies,
the database did not include information regarding the pregnant women’s indication
for montelukast, and the extraction of information from a prescription database may
be a poor proxy for actual use of medications. A separate prospective cohort study
of 180 montelukast-exposed pregnancies reported the same findings that montelu-
kast did not increase the risk of major congenital anomalies.63 Although data about ef-
fects of montelukast on congenital abnormalities during pregnancy are limited, when
combined these reports consistently suggest that montelukast is probably safe as an
add-on controller medication to achieve good symptom control in pregnancy.

Anticholinergics
Anticholinergic agents include the short-acting muscarinic antagonist (SAMA) ipra-
tropium and long-acting muscarinic antagonists (LAMAs) including tiotropium. Anti-
cholinergics induce bronchodilation through the inhibition of muscarinic receptors in
smooth muscle. LAMAs are recommended as add-on therapy for moderate to severe
persistent asthma, due to their ability to reduce asthma exacerbations and improve
asthma control.64 Nebulized ipratropium with b-agonists has been recommended
for the management of acute, severe asthma not responding to b-agonists alone.65
No well-controlled clinical studies of tiotropium have been specifically performed in
pregnant women.

Theophylline
Theophylline previously was a cornerstone of asthma medication because of its bron-
chodilator and anti-inflammatory activity; however, its use has decreased in recent de-
cades due to the introduction of ICSs and concerns regarding its toxicity and side
effect profile.66 Thus, theophylline is no longer recommended as a first-line therapy
for asthma and is only recommended as an alternative add-on controller therapy for
178 Cusack et al

moderate to severe asthma. Theophylline has previously been used in the treatment of
asthma during pregnancy with no evidence of teratogenic effects; however, pregnant
women were significantly more likely to discontinue theophylline than inhaled beclo-
methasone due to increased rate of side effects (6 of 194 discontinued in the beclo-
methasone group, 17 of 190 in the theophylline group; P 5 0.016).38 During
theophylline treatment in all adults, however, blood levels should be monitored
because the risk of toxic reactions increases when the serum theophylline level is
higher than the therapeutic range of 10 to 20 mg/mL.67

Anti-IgE Therapy
Omalizumab is a recombinant monoclonal anti-IgE antibody that binds specifically to
free human immunoglobulin E (IgE) in the blood and is approved as an add-on therapy
for the treatment of moderate to severe allergic asthma despite adequate ICSs.9 An-
imal studies using subcutaneous doses of omalizumab up to 10 times the maximum
human dose found no evidence of fetal harm in cynomolgus monkeys.68
The Observational Study of the Use and Safety of Xolair (omalizumab) during Preg-
nancy Trial (EXPERT) examined the association between omalizumab and congenital
anomalies in 230 pregnancies to compare exposed pregnancies with a disease-
matched population of pregnant women with moderate to severe asthma.69 The rates
of major congenital anomalies were similar in both groups (8.1% in the omalizumab-
exposed group vs 8.9% in the unexposed group) with the most common major
congenital anomalies in the exposed group being torticollis (2.2%), hydronephrosis
(1.3%), and hypospadias (0.9%), and the most common major congenital anomalies
in the unexposed group being cardiac (2.8%), musculoskeletal (1.2%), and urinary
system (1.1%) anomalies with no unique system anomaly found within the exposed
group alone. Therefore, this study does provide reassurance regarding the lack of
teratogenic risk of omalizumab and the safety of continued use of omalizumab in
women with improved asthma control and reduced exacerbations before pregnancy.
Therefore, for women established on omalizumab before pregnancy, if the benefits
outweigh the risks, omalizumab therapy may be continued; however, it is not currently
recommended to start omalizumab in pregnant women.

Anti-Interleukin-5, Anti-Interleukin-4/13, and Anti-Thymic Stromal Lymphopoietin

Monoclonal Antibody Therapies
Interleukin (IL)-5 is a key cytokine involved in the recruitment, activation, and survival
of eosinophils, and anti-IL-5 biological therapies reduce eosinophilic inflammation by
inhibiting this pathway.70 There are 3 monoclonal antibody (mAb) anti-IL-5 therapies
that are approved for use in severe eosinophilic asthma uncontrolled despite maximal
therapy (high-dose ICS or medium-dose ICS-LABA, and 2 or more exacerbations per
year requiring OCS or chronic OCS use): mepolizumab and reslizumab, which bind to
IL-5 preventing it from binding to its receptor on eosinophils, and benralizumab, which
binds to the a subunit of the IL-5 receptor resulting in direct and rapid near depletion of
eosinophils. Animal studies of mepolizumab (monkeys),71 reslizumab (mice and rab-
bits),72 and benralizumab (monkeys)73 found no teratogenic effects. The safety and ef-
ficacy of all 3 anti-IL-5 agents in pregnant women is unknown because pregnancy was
an exclusion criterion for all the clinical trials, and pregnancy registries are ongoing.
Dupilumab is an mAb that binds to the a subunit of the IL-4 receptor blocking
signaling of both IL-4 and IL-13, which are key cytokines in type 2 airway inflammation.
Dupilumab has been approved by the US Food and Drug Administration for the treat-
ment of atopic dermatitis and severe oral steroid-dependent asthma. Animal studies
of dupilumab up to 10 times the maximal human dose in cynomolgus monkeys found
 Use of Asthma Medication During Gestation 179

no fetal harm.74 Three case reports of dupilumab used safely in the treatment of atopic
dermatitis in pregnancy have been reported with no adverse fetal outcomes.75–77
Pregnancy was an exclusion criterion for all the clinical trials of dupilumab, therefore
the safety and efficacy in pregnant women is unknown. The European Medicines
Agency completed a review in 2017 that reported 23 pregnancies in study patients
treated with dupilumab resulting in 8 healthy births (1 twin birth), 2 induced abortions,
6 spontaneous abortions (with 2 of these 6 cases having at least 1 risk factor for abor-
tion), 5 ongoing pregnancies, and 3 pregnancies lost to follow-up.78 The risk of spon-
taneous abortion in pregnancy was similar to that of the general population (11%–
24%).79,80 The risk of medication-associated congenital anomalies could not be deter-
mined, however, due to the low numbers of pregnancies. The EMA report stated that
dupilumab should only be used during pregnancy if the potential benefits outweigh the
potential fetal risks.81 A pregnancy registry for dupilumab in pregnancy is ongoing.
Thymic stromal lymphopoietin (TSLP) is a cytokine produced by the epithelium in
response to external stimuli including viruses, bacteria, and allergens and drives
allergic inflammation early in the inflammatory cascade and may be more suitable
for a broader severe asthma population due to its earlier activity within the inflamma-
tory cascade.82 Tezepelumab is a human anti-TSLP immunoglobulin that binds to hu-
man TSLP and prevents interaction with its receptor83 and has recently been granted
approval by the US Food and Drug Administration for patients with severe asthma.84 A
randomized, double-blind, placebo-controlled study assessed the effect of tezepelu-
mab on annualized rate of asthma exacerbations for patients with severe asthma with
2 or more asthma exacerbations in the year prior despite the use of medium- or high-
dose ICSs and at least 1 additional controller medication, with or without OCSs.85 The
trial showed that annual asthma exacerbation rate was significantly reduced in the
tezepelumab group compared with the placebo group (0.93; 95% CI, 0.8–1.07 with
tezepelumab compared with 2.10; 95% CI, 1.84–2.39 with placebo; P < 0.01), with
a significant reduction in exacerbations observed in the tezepelumab group irrespec-
tive of baseline blood eosinophil levels. These results were observed independent of
baseline blood eosinophil count or other T2 inflammatory biomarkers. Pregnancy was
an exclusion criterion for all studies to date; therefore no safety data are available. An-
imal studies of tezepelumab in cynomolgus monkeys up to 168 times the maximal hu-
man dose found no fetal harm.84 A pregnancy registry for tezepelumab is yet to be
created.
Given the lack of human data for anti-IL-5, anti-IL-4/13, and anti-TSLP biologics and
the risk of teratogenic events, physicians prescribing these medications to women of
reproductive age or pregnant should inform the woman regarding the potential effects
of biologics on pregnancy and risks of congenital anomalies.

DISCUSSION

Managing asthma to control the underlying disease and optimizing fetal outcomes
during pregnancy is a challenge, particularly in severe disease. Asthma may adversely
affect both maternal quality of life and perinatal outcomes including congenital anom-
alies. Optimal management of asthma during pregnancy is imperative to reduce fetal
risk of congenital anomalies associated with severe exacerbations. Owing to the
increasing prevalence of asthma worldwide, it is imperative that physicians are aware
of the potential teratogenic effect severe asthma with exacerbations can have on a
developing fetus, as well as the potential teratogenic risk of antiasthma medications,
to allow physicians determine the optimal therapy for their pregnant patient and
ensure the pregnant women is educated regarding the importance of continuing
180 Cusack et al

therapy during pregnancy. Most human clinical drug trials exclude pregnant asthmatic
women, thereby limiting our knowledge of the effect asthma medications can have on
the developing fetus. This phenomenon is not unique to asthma, however, because
more than 80% of pregnant women are prescribed at least 1 prescription or over-
the-counter medication during pregnancy.86 The lack of clinical trials in pregnant
women with asthma can result in pregnant women and health care workers overesti-
mating the teratogenic risk of asthma medications. A core part of improving the health
of pregnant women is ensuring they are appropriately engaged and included in clinical
research studies because this will allow future pregnant women to make evidence-
based decisions regarding their disease and treatment.
Most small prospective studies showed no certain teratogenic effect of antiasthma
medications. Several retrospective studies suggested associations with some specific
malformations, but the scientific value of these studies is low. Some large studies
demonstrated a relatively weak association between the use of antiasthma drugs
and any congenital malformation and specifically ICS medications and cardiovascular
anomalies and OCS and orofacial anomalies. There seems to be no specificity with re-
gard to type of antiasthma drug, which makes it likely that a confounder such as
maternal asthma or an asthma exacerbation causes anomalies most likely via hypoxia.
A low priority should be placed on stepping down therapy in preparation for, or during
pregnancy. Instead, pregnant women should be educated on the benefits and safety
of usual controller medications particularly ICSs, and the increased risk of asthma ex-
acerbations with poor adherence.
Women with severe asthma may require the use of biological therapies such as
omalizumab, mepolizumab, reslizumab, benralizumab, dupilumab, and in the future
tezepelumab to control their asthma, and the risk of continuing treatment during preg-
nancy or even commencing treatment in unwell pregnant women with severe asthma
will need to be assessed. The randomized clinical trials that supported the approval of
these medications for the treatment of severe asthma excluded pregnant women,
therefore prospective data regarding their safety and efficacy are limited. Observa-
tional data for omalizumab shows no association between omalizumab treatment
and increased risk of congenital anomalies; however, the interpretation of these
data are limited due to small sample size and the presence of confounding factors
such as asthma severity on perinatal outcomes. Pregnancy registries are ongoing
for mepolizumab, reslizumab, benralizumab, and dupilumab; however, there are
currently no published human data available, and therefore data are lacking regarding
their teratogenic risks in pregnancy. Clinicians need to be aware of the risks of severe
asthma in pregnant women, and the lack of available data regarding these agents to
ensure they can appropriately consider the risks and benefits of these treatments dur-
ing pregnancy, and relay this information to pregnant mothers and women of child-
bearing age. To adequately determine the safety of these medications in
pregnancy, human data are critical, therefore clinicians are encouraged to enroll
women who require or receive these treatments during pregnancy into the relevant
pregnancy registries. High-quality randomized controlled trials of these agents in
pregnancy are also required to strengthen the evidence base and inform future guide-
lines for asthma management in pregnancy.

SUMMARY

Although there are concerns regarding the use of any medications during pregnancy,
particularly the first trimester, the benefits of actively treating asthma and reducing the
risks of exacerbations markedly outweigh the risks of congenital anomalies. Given the
 Use of Asthma Medication During Gestation 181

evidence for adverse outcomes including congenital anomalies associated with un-
controlled asthma during pregnancy, a low priority should be placed on stepping
down therapy, and ICSs should not be stopped in preparation for or during pregnancy.
High-quality randomized controlled trials are required to strengthen the evidence base
and inform future guidelines for asthma management in pregnancy; specifically, safety
studies regarding the use of biological therapies in severe asthma in pregnancy are
needed urgently.

CLINICS CARE POINTS

 The available safety data for asthma medications in pregnancy and congenital anomaly risk
are overall reassuring, particularly for ICSs and b-agonists
 The risk of congenital anomalies due to severe exacerbations and poorly controlled asthma
can be reduced with good asthma control
 Pregnant women overestimate the risk of asthma medications resulting in congenital
anomalies
 Physicians should discuss risk and benefit of asthma medications with women to ensure they
understand the risks of discontinuing asthma medications during pregnancy and the risk of
asthma exacerbations resulting in congenital anomalies
 Further studies for biological therapies in pregnant women with severe asthma are needed

DISCLOSURE

The authors have no relevant affiliations or financial involvement with any organization
or entity with a financial interest in or financial conflict with the subject matter or ma-
terials discussed in the manuscript. This includes employment, consultancies, hono-
raria, stock ownership or options, expert testimony, grants or patents received or
pending, or royalties.

REFERENCES

1. Cohen JM, Bateman BT, Huybrechts KF, et al. Poorly controlled asthma during
pregnancy remains common in the United States. J Allergy Clin Immunol In Pract
2019;7(8):2672–80. e2610.
2. Sawicki E, Stewart K, Wong S, et al. Medication use for chronic health conditions
by pregnant women attending an Australian maternity hospital. Aust N Z J Obstet
Gynaecol 2011;51(4):333–8.
3. Rejnö G, Lundholm C, Gong T, et al. Asthma during pregnancy in a population-
based study-pregnancy complications and adverse perinatal outcomes. PLoS
One 2014;9(8).
4. Kwon HL, Belanger K, Bracken MB. Asthma prevalence among pregnant and
childbearing-aged women in the United States: estimates from national health
surveys. Ann Epidemiol 2003;13(5):317–24.
5. Hansen C, Joski P, Freiman H, et al. Medication exposure in pregnancy risk eval-
uation program: the prevalence of asthma medication use during pregnancy. Ma-
tern child Health J 2013;17(9):1611–21.
6. Wang G, Murphy VE, Namazy J, et al. The risk of maternal and placental compli-
cations in pregnant women with asthma: a systematic review and meta-analysis.
J Maternal-Fetal Neonatal Med 2014;27(9):934–42.
182 Cusack et al

7. Kim S, Kim J, Park SY, et al. Effect of pregnancy in asthma on health care use and
perinatal outcomes. J Allergy Clin Immunol 2015;136(5):1215–23. e1216.
8. Murphy V, Namazy J, Powell H, et al. A meta-analysis of adverse perinatal out-
comes in women with asthma. BJOG: An Int J Obstet Gynaecol 2011;118(11):
1314–23.
9. Global Strategy for Asthma Management and Prevention. Global Initiative for
Asthma 2020.
10. Dombrowski M, Schatz M. ACOG practice bulletin: clinical management guide-
lines for obstetrician-gynecologists number 90, February 2008: asthma in preg-
nancy. Obstet Gynecol 2008;111(2 Pt 1):457–64.
11. Al Ghobain MO, AlNemer M. Assessment of knowledge and education relating to
asthma during pregnancy among women of childbearing age. Asthma Res Pract
2018;4(1):1–5.
12. Powell H, McCaffery K, Murphy VE, et al. Psychosocial outcomes are related to
asthma control and quality of life in pregnant women with asthma. J Asthma
2011;48(10):1032–40.
13. Chambers K. Asthma education and outcomes for women of childbearing age.
Case manager 2003;14(6):58–61.
14. Lim AS, Stewart K, Abramson MJ, et al. Management of asthma in pregnant
women by general practitioners: a cross sectional survey. BMC Fam Pract
2011;12(1):1–7.
15. Rocklin RE. Asthma, asthma medications and their effects on maternal/fetal out-
comes during pregnancy. Reprod Toxicol 2011;32(2):189–97.
16. Yland JJ, Bateman B, Huybrechts KF, et al. Fetal Outcomes Among Women with
Asthma during Pregnancy: Evidence from a Large Healthcare Database in the
United States. J Allergy Clin Immunol 2019;143(2):AB422.
17. Garne E, Hansen AV, Morris J, et al. Use of asthma medication during pregnancy
and risk of specific congenital anomalies: a European case-malformed control
study. J Allergy Clin Immunol 2015;136(6):1496–502. e1497.
18. 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):1379–84. e1371.
19. Crane JP, LeFevre ML, Winborn RC, et al. A randomized trial of prenatal ultraso-
nographic screening: impact on the detection, management, and outcome of
anomalous fetuses. Am J Obstet Gynecol 1994;171(2):392–9.
20. Ramsay M. Genetic and epigenetic insights into fetal alcohol spectrum disorders.
Genome Med 2010;2(4):1–8.
21. Torfs CP, Christianson RE, Iovannisci DM, et al. Selected gene polymorphisms
and their interaction with maternal smoking, as risk factors for gastroschisis. Birth
Defects Res A: Clin Mol Teratology 2006;76(10):723–30.
22. Mossey PA, Little J, Munger RG, et al. Cleft lip and palate. Lancet 2009;
374(9703):1773–85.
23. Hyoun SC, Obic an SG, Scialli AR. Teratogen update: methotrexate. Birth Defects
Res Part A: Clin Mol Teratology 2012;94(4):187–207.
24. Diav-Citrin O, Shechtman S, Tahover E, et al. Pregnancy outcome following in
utero exposure to lithium: a prospective, comparative, observational study. Am
J Psychiatry 2014;171(7):785–94.
25. Veroniki AA, Cogo E, Rios P, et al. Comparative safety of anti-epileptic drugs dur-
ing pregnancy: a systematic review and network meta-analysis of congenital mal-
formations and prenatal outcomes. BMC Med 2017;15(1):1–20.
 Use of Asthma Medication During Gestation 183

26. Shanks N, Greek R, Greek J. Are animal models predictive for humans? Philos
Ethics humanities Med 2009;4(1):1–20.
2.. Schardein JL. Drugs as teratogens. Cleveland: CRC press; 1976.
28. Robijn AL, Barker D, Gibson PG, et al. Factors Associated with Nonadherence to
Inhaled Corticosteroids for Asthma During Pregnancy. The J Allergy Clin Immunol
In Pract 2021;9(3):1242–52. e1241.
29. Schatz M, Dombrowski MP, Wise R, et al. The relationship of asthma medication
use to perinatal outcomes. J Allergy Clin Immunol 2004;113(6):1040–5.
30. Murphy VE, Clifton VL, Gibson PG. Asthma exacerbations during pregnancy:
incidence and association with adverse pregnancy outcomes. Thorax 2006;
61(2):169–76.
31. Abdullah K, Zhu J, Gershon A, et al. Effect of asthma exacerbation during preg-
nancy in women with asthma: a population-based cohort study. Eur Respir J
2020;55(2).
32. Breton M-C, Martel M-J, Vilain A, et al. Inhaled corticosteroids during pregnancy:
a review of methodologic issues. Respir Med 2008;102(6):862–75.
33. Schatz M, Zeiger RS, Harden K, et al. The safety of asthma and allergy medica-
tions during pregnancy. J Allergy Clin Immunol 1997;100(3):301–6.
34. Silverman M, Sheffer A, Diaz PV, et al. Outcome of pregnancy in a randomized
controlled study of patients with asthma exposed to budesonide. Ann Allergy
Asthma Immunol 2005;95(6):566–70.
35. Bakhireva LN, Jones KL, Schatz M, et al. Asthma medication use in pregnancy
and fetal growth. J Allergy Clin Immunol 2005;116(3):503–9.
36. Perlow JH, Montgomery D, Morgan MA, et al. Severity of asthma and perinatal
outcome. Am J Obstet Gynecol 1992;167(4):963–7.
37. Alexander S, Dodds L, Armson BA. Perinatal outcomes in women with asthma
during pregnancy. Obstet Gynecol 1998;92(3):435–40.
38. Dombrowski MP, Schatz M, Wise R, et al. Randomized trial of inhaled beclome-
thasone dipropionate versus theophylline for moderate asthma during preg-
nancy. Am J Obstet Gynecol 2004;190(3):737–44.
39. Dombrowski MP, Brown CL, Berry SM. Preliminary experience with triamcinolone
acetonide during pregnancy. J Maternal-Fetal Med 1996;5(6):310–3.
40. Källén B, Rydhstroem H, Åberg A. Congenital malformations after the use of
inhaled budesonide in early pregnancy. Obstet Gynecol 1999;93(3):392–5.
41. Källén B, Olausson PO. Use of anti-asthmatic drugs during pregnancy. 1.
Maternal characteristics, pregnancy and delivery complications. Eur J Clin Phar-
macol 2007;63(4):363–73.
42. Källén BA, Olausson PO. Maternal drug use in early pregnancy and infant cardio-
vascular defect. Reprod Toxicol 2003;17(3):255–61.
43. Namazy J, Schatz M, Long L, et al. Use of inhaled steroids by pregnant asthmatic
women does not reduce intrauterine growth. J Allergy Clin Immunol 2004;113(3):
427–32.
44. Blais L, Beauchesne M-F, Rey É, et al. Use of inhaled corticosteroids during the
first trimester of pregnancy and the risk of congenital malformations among
women with asthma. Thorax 2007;62(4):320–8.
45. Ericson A, Källén B. Use of drugs during pregnancy—unique Swedish registra-
tion method that can be improved. Inf Swedish Med Prod agency 1999;1:8–11.
46. Olesen C, Thrane N, Nielsen GL, et al. A population-based prescription study of
asthma drugs during pregnancy: changing the intensity of asthma therapy and
perinatal outcomes. Respiration 2001;68(3):256–61.
184 Cusack et al

47. Blais L, Beauchesne M-F, Lemière C, et al. High doses of inhaled corticosteroids
during the first trimester of pregnancy and congenital malformations. J Allergy
Clin Immunol 2009;124(6):1229–34. e1224.
48. Norjavaara E, de Verdier MG. Normal pregnancy outcomes in a population-
based study including 2968 pregnant women exposed to budesonide.
J Allergy Clin Immunol 2003;111(4):736–42.
49. Gluck PA, Gluck JC. A review of pregnancy outcomes after exposure to orally
inhaled or intranasal budesonide. Curr Med Res Opin 2005;21(7):1075–84.
50. Suissa S, Ernst P, Boivin J-F, et al. A cohort analysis of excess mortality in asthma
and the use of inhaled beta-agonists. Am J Respir Crit Care Med 1994;149(3):
604–10.
51. Garne E, Vinkel Hansen A, Morris J, et al. Risk of congenital anomalies after expo-
sure to asthma medication in the first trimester of pregnancy–a cohort linkage
study. BJOG: An Int J Obstet Gynaecol 2016;123(10):1609–18.
52. Eltonsy S, Kettani F-Z, Blais L. Beta2-agonists use during pregnancy and peri-
natal outcomes: a systematic review. Respir Med 2014;108(1):9–33.
53. Cossette B, Beauchesne M-F, Forget A, et al. Relative perinatal safety of salme-
terol vs formoterol and fluticasone vs budesonide use during pregnancy. Ann Al-
lergy Asthma Immunol 2014;112(5):459–64.
54. Satia I, Cusack R, O’Byrne P. Paradigm shift in the management of mild asthma:
Focus toward a patient centered approach. Can J Respir Crit Care Sleep Med
2020;4(1):55–60.
55. Cusack RP, Satia I, O’Byrne PM. Asthma maintenance and reliever therapy:
Should this be the standard of care? Ann Allergy Asthma Immunol 2020;
125(2):150–5.
56. Eltonsy S, Forget A, Beauchesne M-F, et al. Risk of congenital malformations for
asthmatic pregnant women using a long-acting b2-agonist and inhaled cortico-
steroid combination versus higher-dose inhaled corticosteroid monotherapy.
J Allergy Clin Immunol 2015;135(1):123–30. e122.
57. Park-Wyllie L, Mazzotta P, Pastuszak A, et al. Birth defects after maternal expo-
sure to corticosteroids: prospective cohort study and meta-analysis of epidemio-
logical studies. Teratology 2000;62(6):385–92.
58. Skuladottir H, Wilcox AJ, Ma C, et al. Corticosteroid use and risk of orofacial
clefts. Birth Defects Res Part A: Clin Mol Teratology 2014;100(6):499–506.
59. Howley MM, Papadopoulos EA, Van Bennekom CM, et al. Asthma Medication
Use and Risk of Birth Defects: National Birth Defects Prevention Study, 1997–
2011. J Allergy Clin Immunol In Pract 2020;8(10):3490–9.e9.
60. Blais L, Kettani F-Z, Forget A, et al. Asthma exacerbations during the first
trimester of pregnancy and congenital malformations: revisiting the association
in a large representative cohort. Thorax 2015;70(7):647–52.
61. Spector SL. Safety of antileukotriene agents in asthma management. Ann Allergy
Asthma Immunol 2001;86(6):18–23.
62. Cavero-Carbonell C, Vinkel-Hansen A, Rabanque-Hernández MJ, et al. Fetal
exposure to montelukast and congenital anomalies: a population based study
in Denmark. Birth defects Res 2017;109(6):452–9.
63. Sarkar M, Koren G, Kalra S, et al. Montelukast use during pregnancy: a multi-
centre, prospective, comparative study of infant outcomes. Eur J Clin Pharmacol
2009;65(12):1259–64.
64. Kim LH, Saleh C, Whalen-Browne A, et al. Triple vs Dual Inhaler Therapy and
Asthma Outcomes in Moderate to Severe Asthma: A Systematic Review and
Meta-analysis. JAMA 2021;325(24):2466–79.
 Use of Asthma Medication During Gestation 185

65. Busse WW. NAEPP expert panel report: managing asthma during pregnancy:
recommendations for pharmacologic treatment—2004 update. J Allergy Clin Im-
munol 2005;115(1):34–46.
66. Weinberger M, Hendeles L. Theophylline in asthma. N Engl J Med 1996;334(21):
1380–8.
67. Barnes PJ. Theophylline. Am J Of Respir And Crit Care Med 2013;188(8):901–6.
68. Genentech. Xolair (omalizumab): full prescribing information. Available at: https://
www.gene.com/download/pdf/xolair_prescribing.pdf. Accessed.
69. Namazy JA, Blais L, Andrews EB, et al. Pregnancy outcomes in the omalizumab
pregnancy registry and a disease-matched comparator cohort. J Allergy Clin Im-
munol 2020;145(2):528–36, e521.
70. Yancey SW, Keene ON, Albers FC, et al. Biomarkers for severe eosinophilic
asthma. J Allergy Clin Immunol 2017;140(6):1509–18.
71. Glaxosmithkline. Nucala (mepolizumab): summary of product characteristics.
2021.
72. Hom S, Pisano M. Reslizumab (Cinqair): an Interleukin-5 antagonist for severe
asthma of the eosinophilic phenotype. P T 2017;42(9):564.
73. Astrazeneca. Fasenra (benralizumab): prescribing information. Available at:
https://www.azpicentral.com/fasenra/fasenra.pdf#page51. Accessed.
74. Regeneron. Dupixent (dupilumab): prescribing information. Available at: https://
www.regeneron.com/sites/default/files/Dupixent_FPI.pdf. Accessed.
75. Kage P, Simon J, Treudler R. A case of atopic eczema treated safely with dupilu-
mab during pregnancy and lactation. J Eur Acad Dermatol Venereol 2020;34(6):
e256–7.
76. Mian M, Dunlap R, Simpson E. Dupilumab for the treatment of severe atopic
dermatitis in a pregnant patient: A case report. JAAD Case Rep 2020;6(10):1051.
77. Lobo Y, Lee RC, Spelman L. Atopic Dermatitis Treated Safely with Dupilumab dur-
ing Pregnancy: A Case Report and Review of the Literature. Case Rep Dermatol
2021;13(2):248–56.
78. European Medicines Agency (EMA): assessment report; dupilumab. 2017.
79. Knudsen UB, Hansen V, Juul S, et al. Prognosis of a new pregnancy following
previous spontaneous abortions. Eur J Obstet Gynecol Reprod Biol 1991;
39(1):31–6.
80. Gray RH, Wu LY. Subfertility and risk of spontaneous abortion. Am J Public Health
2000;90(9):1452.
81. European Medicines Agency (EMA): Summary of product characteristics. 2020.
82. Cusack RP, Whetstone CE, Xie Y, et al. Regulation of Eosinophilia in Asthma—
New Therapeutic Approaches for Asthma Treatment. Cells 2021;10(4):817.
83. Kabata H, Moro K, Fukunaga K, et al. Thymic stromal lymphopoietin induces
corticosteroid resistance in natural helper cells during airway inflammation. Nat
Commun 2013;4(1):1–10.
84. Astrazeneca. Tezspire(tezepelumab) prescribing information: 2021.
85. Menzies-Gow A, Corren J, Bourdin A, et al. Tezepelumab in Adults and Adoles-
cents with Severe, Uncontrolled Asthma. N Engl J Med 2021;384(19):1800–9.
86. Lupattelli A, Spigset O, Twigg MJ, et al. Medication use in pregnancy: a cross-
sectional, multinational web-based study. BMJ open 2014;4(2):e004365.