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ISSN: 0032-5481 (print), 1941-9260 (electronic)

Postgrad Med, 2015; Early Online: 110

DOI: 10.1080/00325481.2015.1016386

REVIEW

Asthma in pregnancy: physiology, diagnosis, and management

William Kelly1, Ali Massoumi2 and Angeline Lazarus3
1
Uniformed Services University, Bethesda, MD, USA, 2Private Practice, Bethesda, MD, USA, and 3Walter Reed Military Medical Center,
Bethesda, MD, USA

Abstract Keywords
Long-acting b-agonist, short-acting
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Asthma is a common, potentially serious, medical condition that affects an estimated 8% of

pregnant patients, with 4% of all pregnant patients experiencing an exacerbation in the past b-agonist, inhaled corticosteroids,
year. Practitioners must be able to diagnose, educate, and treat such patients as they undergo pregnancy
significant physiological and immunologic change. But staying current can be challenging given
over 3000 citations for asthma and pregnancy in a recent PubMed search, with 750 described History
as review articles. Patients have even more difficulty navigating information, with 29 million
Received 10 September 2014
Google search results for this same query and 1.2 million alone for the question whether
Accepted 16 October 2014
asthma medications are safe during pregnancy. This review provides brief answers to important
Published online 23 February 2015
management questions followed by supporting background literature.

Introduction for our article included prospective and retrospective studies

For personal use only.

and review articles. Patient education section includes web-

Management of asthma is crucial to the health of any patient,
and its significance is heightened when the well-being of the
fetus is involved as well. The prevalence of asthma in pregnant
women has been reported in 3.7%8.4% or 200,000
376,000 women annually in the USA. About 10% of patients
have an attack during labor, and status asthmaticus has affected
0.2% of pregnancies [1,2]. As such, asthma is one of the most
common medical conditions that may complicate a pregnancy
and the most common pulmonary disorder. Despite increased
prevalence of the disease, the majority of asthmatics have
uncomplicated pregnancies with no long-term manifestations.
However, uncontrolled asthma and its exacerbations can lead
to complications during the peripartum period and to increased
morbidity and mortality of the mother and fetus. With greater
awareness, diagnosis, monitoring, and timely implementation
of therapy, these complications can be averted significantly [3].
This clinical review focuses on physiology, diagnosis, and
management of asthma in pregnancy. The National Library of
Medicines MEDLINE was used to conduct a search using
the term asthma and pregnancy. Criteria for inclusion of
articles included data outlining respiratory physiological
changes that are reported in pregnancy in healthy individuals
and in asthmatics. Additional information regarding diagnos-
tic criteria and management guidelines were taken from the
recommendations of the expert panel from the National
Asthma Education and Prevention Program (NAEPP), Global
Strategy for Asthma Management, and American Congress of
Obstetrics and Gynecology websites. The literature review
sites from leading professional organizations that are focused
on asthma education.
Normal physiologic changes of pregnancy
In a normal pregnancy, respiratory function is affected as a
manifestation of hormonal changes as well as the enlarging
uterus. With the latter, there is an elevation of the diaphragm
by 45 cm, which leads to a near 20% reduction in the func-
tional residual capacity (FRC the volume of air that remains
after normal exhalation) [4,5]. However, lung excursion does
not diminish which, along with an increase in respiratory
rate, allows for the increase in minute ventilation associated
with pregnancy [5].
Additionally, the decrease in FRC is offset by a smaller
expansion of the chest wall cavity. Clinical manifestation of
the drop in FRC is a loss of oxygen reservoir function at the
end of expiration. As such, rapid desaturation may occur
during episodes of hypopnea or during recumbent position as
diaphragm elevation is at its greatest [5].
Signs of rhinitis, soft systolic flow murmurs or split heart
sounds, prominent jugular venous pressure, and mild periph-
eral edema are common in pregnancy and are not helpful nor
are of concern [6].
Fortunately, airway function and resistance remain mostly
unchanged during pregnancy. Thus, maneuvers that assess air
flow such as FEV1 (the volume of air exhaled during the first
second of a forced expiratory maneuver) and peaked expiratory

Correspondence: Angeline Lazarus, MD, MACP, FCCP, Professor of Medicine, Walter Reed Military Medical Center, Pulmonary Medicine, Bethesda,
MD, USA. E-mail: angeline.a.lazarus.civ@mail.mil
 2015 Informa UK Ltd.
 2 W. Kelly et al.
flow rate (PEFR- the maximum flow during forced expiration)
remain unchanged [7]. These two markers remain valuable
tools in diagnosing and monitoring asthma during pregnancy.
A marked increase in respiratory drive and minute ventila-
tion is the most obvious physiologic change that appears to
increase from week 13 of gestation through week 37, and
returns to normal by 24 weeks after delivery [5]. These
changes are thought to be a manifestation of progesterones
effect on the respiratory center either by direct stimulation or
by increasing its sensitivity to carbon dioxide [5,8].
This adaptive respiratory mechanism is in response to the
CO2 production which can increase by one-third to one-half
in the last trimester. Both components of minute ventilation
(respiratory rate  tidal volume) are increased. Tidal volume
(the volume of air that is exchanged with normal respiration)
goes up by 30%35% [5]. The net result is an increase in
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minute ventilation by 50%, and a subsequent respiratory
alkalosis with renal bicarbonate wasting as compensation.
A typical blood gas will reveal a PaCO2 range between
28 and 32 mmHg, but pH is near a normal of 7.407.45 due
to concomitant metabolic acidosis. Knowledge of these val-
ues is important as normalization of PaCO2 may actually
represent CO2 retention and possible impending respiratory
failure. Alternatively, chronic elevation may simply represent
a state of uncontrolled asthma. Regardless of the cause, an
increase in maternal PCO2 will affect the fetuss ability to
For personal use only.
excrete acid and will ultimately lead to fetal acidosis [4].
Asthma during pregnancy
Hormonal effects on the pathophysiology of asthma have
been studied, but there fails to be any consistent and convinc-
ing evidence for it [5]. Clinical manifestations of the disease
have been equally varied, with subjective assessment of dis-
ease having large fluctuations. Despite this, some patterns
have emerged leading the NAEPP Working Group to make
the general conclusions that about one-third of maternal
asthma cases will improve during pregnancy, one-third cases
remain unchanged, and the remainder will worsen [5].
Asthma severity during past pregnancies may predict disease
activity during the current pregnancy [9].
The NAEPP last provided an update on management of
asthma during pregnancy in 2007 [10]. More recently, the
American Congress of Obstetricians and Gynecologists
(ACOG) in 2012 reaffirmed their earlier guidelines which
largely mirrored the NAEPP recommendations [11]. All guide-
lines emphasize that the benefits of treating asthmatic pregnant
women outweigh any potential medication side effects, as
inadequate control poses a greater risk to the fetus [2,11].
Complications of asthma
Is asthma associated with worse pregnancy outcomes?
Yes, but patients should be reassured that the vast majority of
pregnancies end well and that appropriate management likely
improves outcomes.
Many studies associate maternal asthma with complica-
tions, but have been retrospective, failed to adjust for asthma
Postgrad Med, 2015; Early Online:110
severity, or limited by small size. In a 15,000 patient cohort
study [12], uncontrolled asthma was associated with an
increase in spontaneous abortion (odds ratio [OR] = 1.41,
95% confidence interval [CI]: 1.331.49). Murphy et al.s
systemic reviews and meta-analyses [13,14] suggest that
asthma is associated with preterm birth (relative risk
[RR] = 1.41, 95% CI: 1.231.62). Other associations include
low birth weight (RR = 1.46, 95% CI: 1.221.75), small size
for gestational age (RR = 1.21, 95% CI: 1.141.31), and
preeclampsia (RR = 1.54, 95% CI: 1.321.81). Patients with
moderate or severe asthma are more likely to have exacerba-
tions and small or low birth weight babies. Perinatal mortality
in the neonatal period (RR = 1.25, 95% CI: 1.051.50), but
not stillbirths (RR = 1.06, 95% CI: 0.91.25), was increased.
A large observational Swedish study of nearly 37,000 pregnant
women with reported asthma, from 1984 to 1995, was
compared to over 1.3 million Swedish pregnancies without
asthma. Maternal asthma was associated with increased rates
of preeclampsia, perinatal mortality, preterm births, and low
birth weight [15,16]. Prospective studies have failed to show
an association of preterm delivery with asthma as seen with
the retrospective studies. However, Bracken et al. [17] did
reveal that those with daily or moderate persistent symptoms
were at a significantly higher risk of small gestational age and
preeclampsia. Dombrowski et al. [18] found only increased
risk of cesarean delivery rates in those with moderate-to-
severe asthma. In both studies, oral corticosteroid use was
associated with low gestation age.
Malformations (birth defects) are of particular concern
for expecting parents. The largest and most recent review [19]
of 56,000 pregnant patients with asthma showed an associa-
tion with cleft lip with or without cleft palate infants
(RR = 1.30, 95% CI: 1.011.68) and neonatal death
(RR = 1.49, 95% CI: 1.112.00). But there was no significant
effect of asthma on major malformations (RR = 1.31, 95%
CI: 0.573.02) or stillbirth (RR = 1.06, 95% CI: 0.91.25).
First trimester exacerbations may be associated with more
malformations (12.8 vs 7.9%, adjusted OR [aOR] = 1.48, 95%
CI: 1.042.09) [20]. Although the exact mechanisms leading
to these complications have not been fully delineated, hypoxe-
mia has been theorized as a potential contributor. Given that
umbilical veins have a lower PO2 than the placental venous
channels, any evidence of maternal hypoxemia will lead to
inadequate delivery to the fetus [3,4]. Chronic hypoxemia,
which may be seen in uncontrolled asthma, will ultimately
lead to intrauterine growth restriction and low birth weight.
Good care prevents asthma exacerbations that require oral
corticosteroids, which are in turn associated with preterm
delivery (RR = 1.51, 95% CI: 1.151.98) and low birth
weight (RR = 1.31, 95% CI: 1.041.93) [21]. Reviews sug-
gest that patients who receive active disease management
of their asthma have better outcomes.
Diagnosis
How do you make or confirm the diagnosis of asthma in
a pregnant patient?
Diagnosing asthma in the pregnant patient is the same as
for the nonpregnant patients with two important exceptions:
 DOI: 10.1080/00325481.2015.1016386
(1) Methacholine (or other bronchoprovocation testing) and
(2) allergen skin testing are NOT performed.
The approach to diagnosis of asthma during pregnancy is
not dissimilar to ones approach to any nonpregnant asthmatic
patient. Diagnosis is based on but not limited to the combina-
tion of classic symptoms (wheezing, cough, chest tightness,
shortness of breath), temporal fluctuations (e.g. worse at
night), identification of triggers (e.g. allergens, exercise), and
wheezing on examination (although its absence does not
exclude a diagnosis) [2,11]. A personal history of allergies or
atopy (elevated immunoglobulin (Ig)E to antigens), or family
history of asthma or allergies increases the likelihood of
asthma in patients [22,23]. Patients should be asked about
household tobacco use, occupation, hobbies, pets, and other
environmental exposures. A thorough and candid medication
history is critical as pregnant patients often stop or decrease
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medications when pregnancy is discovered [24,25]. Nonster-
oidal anti-inflammatory drugs (NSAIDs) can exacerbate
asthma [26] and others such as nonselective b-blockers should
be considered contraindicated [27].
As many as one-third of patients with reported asthma
may have been misdiagnosed [28], so a careful medical
records review to confirm past pulmonary function testing
showing reversible obstruction or inducible airway hyper
reactivity is warranted. Wheezing over the upper airway with
inspiratory maneuvers may suggest laryngeal dysfunction.
For personal use only.
But note that 20% of patients can have such vocal cord issues
and asthma at the same time [29].
Spirometry defines asthma as presence of obstruction with
a significant bronchodilator response (i.e. 12% improve-
ment in FEV1 or FVC, plus 200 cc improvement in either)
[30]. If a significant bronchodilator response cannot be
established, it is still reasonable for a trial of therapy if the
remainder of clinical picture is consistent with asthma [11].
Dyspnea of pregnancy, which is described as shortness of
breath at rest and which can occur in up to 70% of pregnan-
cies, is a likely progesterone-mediated phenomenon that can
usually be differentiated from asthma given its lack of
obstruction, cough or wheezing [3,31]. Pregnancy-related
cardiomyopathy is uncommon and usually presents in the last
gestational month [32].
Provoking airway obstruction in a patient with normal
spirometry using inhaled methacholine, cold air, eucapnic
voluntary hyperventilation, exercise, or other agents, is rela-
tively contraindicated and should not be done because of the
theoretical risks of causing a hypoxic asthma exacerbation.
Such bronchoprovocation is avoided in pregnant patients to
avoid the potential of increased bronchospasm and clinical
decompensation and providers may opt for empiric therapy
instead [3]. Skin testing for allergens is generally contraindi-
cated because potent antigens may trigger anaphylaxis and
endanger the mother and fetus [33]. Serum RAST testing for
IgE levels on suspected allergens such as dust mites, animal
dander, pollens, and cockroach can be obtained if desired.
Chest X-rays are not indicated for proven asthma respond-
ing to therapy in any patient, pregnant or not [34], but they
can be obtained if an alternative diagnosis is suspected.
Serum complete blood count, if ordered, may show
anemia due to fluid volume shifts or iron deficiency in
Asthma in pregnancy 3
pregnancy, and may occasionally have a mild eosinophilia
with asthma [35].
Another interesting aspect of maternal asthma is that there
appears to be an association between rhinitis control and
asthmatic symptoms, suggesting that rhinitis control during
pregnancy may help control asthma [15]. This may be diffi-
cult to discriminate from the normal effects of estrogen,
which induces mucosal edema and hypervascularity of the
upper airways during pregnancy [4].
Control of asthma is defined as minimal symptoms during
day or night, no limitations with activity, lack of exacerba-
tions, minimal use of rescue inhalers, and near-normal pulmo-
nary function tests. Thus, spirometry is not only recommended
for the initial assessment but also recommended during
monthly assessment thereafter. Peak expiratory flow meters
can be helpful for monitoring of proven asthma, but are less
reliable for initial diagnosis [36]. Typical PEFR in pregnancy
should be 380550 L/min [3], but each individual needs to
establish their best effort. Maintaining levels > 90% of per-
sonal best is considered optimal control [4]. More intense
ultrasound examinations may be considered at 32 weeks and
beyond for those with uncontrolled disease.
The remaining recommendations parallel those of the
general population. These include avoiding and identifying
triggers, providing adequate education to ensure insight into
the disease, and using a stepwise approach to pharmacologi-
cal therapy [4]. Similarly, the asthma severity classification
is based on the National Institutes of Health classification
system [4].
Treatment of chronic asthma during pregnancy
What is the recommended treatment for pregnant
patients with chronic asthma? How is it different from
nonpregnant patients?
Asthma disease management in pregnant patients is mostly
the same as for nonpregnant patients, with inhaled cortico-
steroids (ICSs) being the preferred long-term controller medi-
cation. However, (1) additional patient education efforts are
required as medication adherence is worse; (2) some medica-
tions within a drug class are preferred because of their
historical safety, such as the ICS budesonide; (3) stepping-
down, or decreasing therapy, is usually deferred until after
delivery; (4) monitoring is more frequent (monthly); and (5)
rarely, medications used around the time of delivery can
affect asthma symptoms.
Education
During pregnancy, patients are less likely to take their
medications and physicians are less likely to prescribe them.
Perhaps due to concerns about side effects, pregnant patients
with asthma have lower adherence to medications [24]. From
pharmacy data [25] of 2000 pregnant patients, asthma pre-
scriptions were less likely to be filled during the first trimester
than during the 3 months prior to pregnancy, with 38% not
being on any medications. Reasons for pregnant patients to
decrease or discontinue medications without discussing with
their doctors include lack of support and information about
 4 W. Kelly et al.
what to do, concerns about the safety of the medications, past
experiences, and desire for an all natural pregnancy [37]. In
one study, pregnant women mistakenly perceived a 42% tera-
togenic risk with oral corticosteroids, 12% risk with ICSs, and
a 5% risk with short-acting b-agonists (SABAs) [38]. Accord-
ingly, another prescription claims data cohort of
112,171 patients showed decreased asthma medication use
from 5 to 13 weeks of pregnancy. It was 23% lower for ICSs,
13% lower for SABAs, and 54% lower for rescue
corticosteroids [15].
Empowering patients is important, since positive beliefs
about asthma, low anxiety, and a perception of good asthma
control have been associated with less exacerbations
(OR = 0.92, 95% CI: 0.850.98) for preterm birth
(OR = 0.84, 95% CI: 0.750.94), C-section without labor
(OR = 0.84, 95% CI: 0.720.97) [38].
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Although regular home monitoring of lung function with
peak flow meters may be challenging and cumbersome for
some, it should be included as part of a comprehensive
asthma action plan [39]. The following websites are available
for patient education regarding asthma management.
http://www.acaai.org/allergist/liv_man/pregnancy/Pages/
default.aspx
http://www.aafa.org/display.cfm?id=8&sub=17&cont=177
http://www.nhlbi.nih.gov/health/public/lung/index.
htm#asthma
For personal use only.
Tobacco cessation
Active smoking is associated with an increased risk of
daytime and nighttime asthma symptoms and fetal growth
abnormalities (small size and lower birth weight) [40].
Additionally second-hand smoke during pregnancy is associ-
ated with subsequent asthma in the child even if the mother
herself does not smoke (RR = 1.34, 95% CI: 1.011.76) [41].
Smoking increases the risk of intensive care unit (ICU)
admission with influenza-like illnesses (RR = 2.77, 95% CI:
1.196.45) [42].
Infection avoidance and vaccination
Viral upper respiratory infections (URIs) are the leading
cause of asthma exacerbations in pregnant women. This was
evidenced in a prospective cohort study [43] of pregnant
women whose self reported symptoms were confirmed
with polymerase chain reaction (PCR) swabs. The results
suggested an increased susceptibility to these infections (inci-
dent rate ratio = 1.77, 95% CI: 1.302.42) as 71% developed
a URI during their pregnancy, resulting in poorer asthma con-
trol/exacerbation in two-thirds, with increased likelihood of
pre-eclampsia. Furthermore, pregnant women have been
identified as an at risk population to influenza, including
H1N1, and routine flu vaccination is recommended [44].
Allergen avoidance
It is pertinent to avoid triggers (irritants, certain foods, medi-
cations like NSAIDs), modify routines (limiting cold, dry air),
and attempt specific environmental controls, when available,
Postgrad Med, 2015; Early Online:110
such as air filtration or special bed covers (animal dander,
dust mite, mold, cockroach) [45].
Exercise triggers
With exercise-induced symptoms, inhaled SABAs 30 minutes
prior along with a warm-up routine may reduce the degree of
bronchospasm [46]. A mask or scarf over the mouth may
help with exercise bronchospasm in cold weather [47].
Nutrition
Obesity while pregnant has been linked to adverse offspring
outcomes including metabolic syndrome, behavioral prob-
lems, and asthma [48]. Obese patients are more likely to have
asthma exacerbations (OR = 1.3, 95% CI: 1.11.7), undergo
C-section (OR = 1.6, 95% CI: 1.33.0), have preeclampsia/
gestational hypertension (OR = 1.7, 95% CI: 1.32.3) and
gestational diabetes (OR = 4.2, 95% CI: 2.86.3) [49].
Pharmacologic therapy: recommendations
and safety
The Global Initiative for Asthma stated that pregnant
women with asthma should be advised that poorly controlled
asthma and exacerbations provide a much greater risk to their
baby than do current asthma treatments [50]. Medications
are never tested on pregnant patients, and most asthma
medications have an US Food and Drug Administration
(FDA) drug classification of C (risk cannot be ruled out)
because there are no controlled studies in pregnant women.
Patients should be fully informed but can be legitimately
reassured that decades of numerous studies support medica-
tion safety.
The medication recommendations that follow are consis-
tent with latest guidelines including NAEPP, National Heart,
Lung, and Blood Institute Expert Panel Report 3 from 2007
[10] (Figure 1), British Thoracic Society/Scottish 2012 [51],
and American Congress of Obstetrics and Gynecology
(ACOG) 2012 reaffirmation of their 2008 guidelines [11].
Treatment is based on disease control and severity, such as
worse pulmonary function (lower FEV1) and more frequent
symptoms disrupting daytime function or sleep or requiring
rescue medication use leading to more (or higher dosages of)
medications. Whereas in nonpregnant patients, the use of
SABA at 20-minute intervals three times during acute exacer-
bation is recommended (Figure 1), pregnant women may
need to seek medical attention sooner. Asthma is not well
controlled and requires more aggressive treatment with any
of the following: (1) symptoms are more frequent than 2 days
per week, (2) nighttime awakenings occur more than twice
per month, (3) there is interference with normal activity,
(4) PEFR is < 80% of personal best value, or (5) systemic
steroids were required for an exacerbation in the past year.
Therapy is stepped up every 1 to 2 weeks if control is not
achieved, with consideration for jumping ahead two steps if
there are significant symptoms.
Step 1: SABA albuterol metered-dose inhaler (90 mg/puff)
2 puffs every 46 hours as needed for the relief of acute
 DOI: 10.1080/00325481.2015.1016386 Asthma in pregnancy 5

Persistent asthma: daily medications1

Intermittent
asthma Consult with an astha specialist if step 4 care or higher is required.
and consider consultation at step 3.

STEP UP if
needed every
1 to 2 weeks
(first check
Step 64 adherence,
Step 4 environmental
Preferred: Preferred: control, and
medium-dose Step 54 high-dose for comorbid
Step 33
ICS ICS conditions)
Preferred: Preferred:
+ +
medium-dose high-dose
Step 22 LABA LABA Assess
ICS ICS control
Preferred: +
Alternative: +
low-dose ICS Alternative: Oral
medium-dose LABA STEP DOWN if
low-dose corticosteroid
Step 1 Alternative: ICS possible
ICS+LABA; or
cromolyn, (usually
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Preferred: low-dose ICS+ +

LTRA or postpartum or
SABA PRN LTRA or either LTRA or
theophylline at least after
theophylline theophylline asthma is well
controlled at
Patient education and environmental control at each step least 3 months)

(1) STEPWISE APPROACH above is slightly modified from NHLBI Expert Panel Report 3, 2007 [10] which is designed to assist, not
replace, clinician decision making. SABA (short acting beta agonist) should be provided to all patients for use as needed for
symptoms. May be up to three treatments at 20-minute intervals if having a severe exacerbation. Shot courses of oral
corticosteroids may be needed. Use of SABA more than 2 days per week for symptoms control (not for prevention of
exercise symptoms) indicates inadequate control and need to step up therapy.
(2) ICS = inhaled corticosteroid. LTRA = leukotriene receptor anatagonist. Of note, STEP 2,3 and 4 guidelines usually state
consider subcutaneous allergen immunotherapy, but in pregnancy this therapy is NOT initiated (though it may at times be
continued if already in progress). Best evidence is for single antigens, in children. See text of article.
(3) STEP 3 guidelines usually list low-dose ICS+LABA as preferred, but author(s) preference is medium-dose ICS in
For personal use only.

pregnancy. LABA = long-acting beta agonist, and should never be used in asthma without also giving inhealed corticosteroids.
(4) STEP 5 and STEP 6 guidelines consider immunomodulation therapy, such as Omalizumab (Xolair), but in pregnancy this
therapy is NOT initiated (though at times may be continued if already in progress). Users must be equipped to deal
with anaphylaxis. See text of article.

Figure 1. Stepwise pharmacological approach to the treatment of chronic asthma.

Reproduced from National Heart, Lung, and Blood Institute website (public domain) [10].

symptoms. Patients should be provided with a spacer device.
Nebulizers offer no advantage [52]. A dose can also be taken
30 minutes before exercise. The need for this rescue inhaler
use (from 0 to up to > 3 times/day) intuitively measures
asthma control and is formally part of the Asthma Control
Test (ACT).
Safety: A study of 259 prospectively studied patients
showed no adverse outcomes in nine categories [53]. In a
Canadian cohort study of 13,117 pregnancies, there was no
association between first trimester SABA use and any of the
1242 malformations noted (aORs = 1.04, 95% CI: 0.921.17)
[54]. Studies that have shown an association with adverse
outcomes have often not accounted for asthma disease
severity. These include the National Birth Defects Prevention
Study casecontrol data [55] from mothers of 2711 infants
with orofacial clefts and 6482 mothers of live-born infants
without birth defects, delivered between 1997 and 2005.
Albuterol use during the periconceptional period was asso-
ciated with cleft lip (aOR = 1.79, 95% CI: 1.072.99) and
cleft palate (aOR = 1.65, 95% CI: 1.062.58). Similarly,
Lin et al. have reported a small increase in congenital heart
defects in one small casecontrol study (n = 22, OR = 2.20,
95% CI: 1.054.61) [56] and an association with gastroschi-
sis in a larger series (OR = 2.06, 95% CI: 1.193.59) [57].
However, another casecontrol study [58] looking at low
birth weight, and a 1828 patient cohort study [59] of low
birth weight, small gestational age, or major congenital
malformations found no associations with b-agonist use. Sys-
tematic reviews of 190 exposures and casecontrol data from
156 exposed infants showed no increased risk of congenital
malformations, preterm delivery, or preeclampsia. Long-
acting b-agonists (LABAs) should always be used in
conjunction with an ICS, ideally as a combination product.
Available agents include salmeterol and formoterol [51], with
salmeterol preferred due to longer history of use.
When SABAs are required more than twice per week, step
up to a daily controller medication is required. Dose ranges
are provided below, but the most important outcome is clinical
response to therapy.
Step 2: ICSs at low dose budesonide initial: 360 mg
twice daily (or any equivalent ICS). Budesonide dose range
is 180600 mg/day in divided doses. Note that there are
different brands and also the dose of dry powder inhalers
(DPIs) is often a little higher than metered-dose inhalers
(hydrofluoroalkane [HFA]). Equivalent fluticasone HFA dose
is 88264mg/day. The best long-term controller medication
is ICSs. By reducing inflammation, they improve symptoms,
decrease disease flares, and increase pulmonary function. In
pregnant patients specifically, ICS has been shown to reduce
acute asthma attacks and reduce the risk of readmission fol-
lowing an exacerbation [59,60]. Budesonide has more gesta-
tional safety data available, earning it an FDA pregnancy
 6 W. Kelly et al.
category B. There is no expectation or evidence that other
ICSs would not behave similarly.
Safety: Concern for side effects of inhaled medications
and, in particular, ICSs has been explored as well, given that
ICSs are the preferred medication for management of asthma.
A Swedish registry provides some reassuring data [61],
including 2968 mothers who reported the use of inhaled
budesonide during early pregnancy and gave birth to infants
of normal gestational age, birth weight, and length, with no
increased rate of stillbirths or multiple births. Data from
the Danish national Birth Cohort [62,63] is also reassuring
in terms of infant outcomes. Authors looked for 17 diseases
in the children of 4000 pregnant asthmatics out to a median
age of 6.2 years. The only finding was of endocrine,
metabolic, and nutritional disorders (hazard ratio = 1.84,
95% CI: 1.132.99). Interestingly, there has effectively been
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a randomized trial of budesonide with 319 pregnancies occur-
ring during a larger trial of 7243 asthma patients, with no
increase in adverse pregnancy outcomes seen [64].
However, high-dose ICSs have raised some safety
concerns. In a Blais cohort study [65], 13,280 significant dif-
ferences in malformations were found with high- versus
Low-dose ICS (aOR = 1.63, 95% CI: 1.022.60). Addition-
ally a Canadian cohort study of low birth weight, preterm
birth, and small for gestational age found no association with
low-dose ICS and a nonsignificant increasing trend with
For personal use only.
doses equivalent to > 200 mg/day budesonide [66]. In con-
trast, a population data from 52,000 patients taking steroids
(in any form) out of 830,000 pregnancies did not show an
association with cleft lip or cleft palates [67,68]. Several stud-
ies failed to show an increased risk of malformations with
ICS use, and in fact, it has been shown that the risk of low
birth weight can be significantly higher in those not on ICS
[4,15,18,69]. Thus, one can reasonably conclude that the risk
of uncontrolled disease far outweighs any potential risks of
standard medical therapy.
As far as alternative controller medications, they are
available but not recommended if ICSs can be tolerated. In a
randomized control trial ICSs (beclomethasone)
versus theophylline, there was no difference in maternal
or fetal outcomes, but the beclomethasone was better toler-
ated [60]. Theophylline also requires frequent drug level
monitoring [70].
Based on one randomized but small study [71] (n = 96),
leukotriene receptor antagonists (LTRAs) were not associated
with an increased risk of pregnancy loss, gestational diabetes,
preeclampsia, low maternal weight gain, preterm delivery,
low Apgar scores, or reduced measures of birth length and
head circumference in infants. But there was a slight
decrease in birth weight, and birth defects were increased
compared to controls without asthma.
Step 3: Medium-dose ICSs. Budesonide > 6001200
mg/day or equivalent (i.e. fluticasone HFA 264440 mg/day).
Asthma guidelines do say or low-dose ICS plus long-acting
b agonist (LABA). Of note LABA monotherapy, without
ICS, is contraindicated because of concerns over increased
serious and fatal adverse events [72]. LABA salmeterol is pre-
ferred the US given longer duration of clinical use compared
Postgrad Med, 2015; Early Online:110
with formoterol. Low-dose ICSs with LTRA or low-dose
ICSs with theophylline are also guideline-acceptable.
Step 4: Medium-dose ICSs. Budesonide > 6001200 mg/
day or equivalent (i.e. fluticasone HFA 264540 mg/day) plus
LABA. In the USA, combination agents include Advair
(fluticasone plus salmeterol) and Symbicort (budesonide plus
formoterol). Again, medium-dose ICSs with an LTRA or
theophylline are listed as alternative controller options.
Step 5: High-dose ICS plus LABA. This is budesonide
> 1200 mg/day or equivalent (i.e. fluticasone HFA > 440
800 mg/day) plus a LABA.
Step 6: Step 5 treatment plus oral systemic glucocorti-
coids. Prednisone, prednisolone, and methylprednisolone
cross the placenta at very low concentration, whereas dexa-
methasone and betamethasone reach the fetus at higher con-
centration. Dose is lowest needed for the shortest amount
of time but consider 40 mg/day prednisone for 514 days.
Safety: Cohort studies by Schatz et al. show an association
of oral corticosteroids and preeclampsia in multivariate analy-
ses (n = 824, OR = 2.0, p = 0.027) [73]. Others show
increased risk of gestational diabetes (12.9 vs 1.5%) and
C-section (38.7 vs 19.2) [74]. For the infants, there is
increased risk of preterm birth (n = 2123, OR = 1.54, 95%
CI: 1.022.33) and birth weight < 2500 g (OR = 1.80, 95%
CI: 1.132.88) [59], including adjustments for asthma
severity. Large reviews support these gestational growth find-
ings, including studies of corticosteroids given for indications
other than asthma [75]. Cleft lip and palate with steroids has
been a concern in animal studies, and a 2000 analysis [76] of
casecontrol studies suggested an association (OR = 3.35,
95% CI: 1.975.69). However, analysis of cohort studies by
the same authors did not show this trend. Furthermore, in a
Danish cohort from 1999-2009, only one (0.08%) out of
1449 primiparous women on inhaled or oral steroids resulted
in an oral birth defect [77]. The same authors reviewed pub-
lished studies to date and RR estimates ranging from
0.8 (95% CI: 0.41.7) to 2.1 (95% CI: 0.59.6) overall and
ORs from 0.6 (95% CI: 0.21.7) to 5.2 (95% CI: 1.517.1)
for oral clefts, all insignificant [77].
Starting immunotherapy during pregnancy is contraindi-
cated because the risk of anaphylaxis is unknown and the
benefits appear minimal [78]. However, women already
receiving allergy shots, on a stable and non-escalating dose,
and who appear to be benefiting from them, can continue
safely based on retrospective patient series [79]. Interestingly,
this has also been shown to be true for sublingual immuno-
therapy [80].
Omalizumab (Xolair), a recombinant DNA-derived mono-
clonal antibody that selectively binds to human IgE, has been
shown to be helpful for non-pregnant, symptomatic asthmatic
patients refractory to standard therapy, but with underlying
perennial allergies and elevated serum IgE (Steps 5 and 6). It
is FDA pregnancy category B, and preliminary data from the
industry-sponsored pregnancy registry (EXPECT study) from
170 pregnancies are reassuring, but this has not yet been pub-
lished. Anaphylaxis is a small but persistent risk (estimated
0.2%), and its weight-based dosing may be challenging given
changes during pregnancy [81].
 DOI: 10.1080/00325481.2015.1016386
Monitoring
Monitoring of asthma should be at least monthly for stable
disease, and in conjunction with obstetric providers routine
assessment of intra-uterine growth. Clinical assessment should
include symptom frequency, quality of life, and rescue inhaler
medication use and technique, peak flow measurements
(if done), and lifestyle modifications, rescue inhaler can
include checklists or quantification, such as the ACT, which
may be useful for confirming controlled asthma [82,83].
Measurement of Fractional Exhaled Nitric Oxide (FENO) is a
non-invasive and often well tolerated procedure, which may
correlate with airway inflammation. Although not routinely
used or available, it may at times serve as an adjunct to
adjusting therapy in asthmatics. In a study of 220 pregnant
patients [84], FENO-based titration as compared to using clini-
Postgraduate Medicine Downloaded from informahealthcare.com by Kainan University on 04/23/15
cal symptom alone resulted in fewer exacerbations (0.288 vs
0.615 per pregnancy), improved quality of life scores, and
decreased neonatal admissions (8% vs 17%, p = 0.046).
Stepping-down of therapy is usually done postpartum to
avoid precipitating problems. An exception may be those
patients doing very well can step down from level 5 or level 6.
Acute exacerbations
Acute asthma exacerbations can be especially distressing for
For personal use only.
both patients and their medical providers. Undertreatment
must be avoided.
A literature review of asthmatic pregnant patients
hospitalized for exacerbation, identified an overall incidence
rate of 6%, with the majority attributed to severe/difficult to
control asthma, viral infections, and non-adherence to
medications [85]. Risk of severe exacerbations in patients
with mild, moderate, and severe asthma is reported as 8%,
47%, and 65%, respectively [86]. In that report, mean
gestational age at presentation was 25.1 9 weeks.
Like with all those with asthmatic exacerbations, therapy
will include close monitoring with supplemental oxygen,
inhaled beta agonists (inhaled anti-cholinergics may be added
as an adjunct), and possibly systemic steroids. Differences in
management include a higher goal oxygen saturation for the
pregnant woman (95% has been suggested) [86,87] and addi-
tion of continuous fetal monitoring.
If an arterial blood gas is obtained, it is important to note
that a normal carbon dioxide level may suggest impending
respiratory failure, as pregnant patients normally have
hypocapnia and respiratory alkalosis due to increased minute
ventilation [88].
Chest radiographic imaging is not contraindicated but not
routinely recommended unless an alternative diagnosis is
considered. If venous thromboembolism is suspected, con-
sider leg ultrasound or ventilationperfusion scan instead of
computed tomography angiogram in order to reduce radiation
risks.
Intravenous aminophylline has been shown to have no
advantage over continuous ICS and does not decrease hospi-
tal stays, and ICS (along with b-agonists and oral steroids)
does decrease readmission rates (33% vs 12%, p < 0.05,
OR = 3.63, 95% CI: 1.0113.08) [87]. Intravenous
Asthma in pregnancy 7
magnesium has been shown to increase lung function and
decrease admissions in children [88].
Admission to the hospital is required if there is a persistent
oxygen requirement, PEFR < 70%, fetal distress, mental
status changes, normal or elevated PCO2, slow response to
medical therapy, or other clinical concerns. Given higher risk
of hypoxemia (as manifestation of decreased FRC) [89], and
laryngeal edema which may complicate intubation (especially
if pre-eclampsia) [90], pregnant patients with asthma exacer-
bation should be admitted to a monitored setting such as an
intensive care unit (ICU). Although pregnant patients with
asthma are just as likely to be admitted as those that are
nonpregnant (24% vs 21%, p = 0.61), they are less likely to
be given systemic steroids in the emergency department
(66% vs 44%, p = 0.002) or discharged with them (38% vs
64%, p = 0.002). One can assume this discrepancy is for
fear of medication toxicity, but inadequate treatment has been
shown to lead to a near 3 fold increase in prolonged symp-
toms (95% CI:1.26.8) [91]. Corticosteroid treatment for
3 to 10 days and outpatient follow up of 5 days, if dis-
charged, has been recommended.
Peripartum asthma care and concerns
Fortunately, 90% of pregnant patients have no symptoms dur-
ing delivery and those who do may only require inhaled
bronchodilators [9]. Adequate hydration is standard care as is
continuing the patients usual asthma medications. When pro-
viding analgesia, NSAIDs can cause problems if the patient
is aspirin-sensitive. Morphine can also cause histamine
release, an effect not seen with fentanyl. C-section rates for
asthma patients are increased [51], and conversely patients
with C-section may have an increased risk of postpartum
asthma exacerbation. For surgery, epidural anesthesia may
have benefits over intubation as in nonpregnant patients.
Patient on chronic or frequent steroids may be at risk of adre-
nal insufficiency which can be prevented with stress dosing
(50 mg hydrocortisone every 6 hours) during labor and for
the first postpartum day.
If medical therapy for postpartum hemorrhage is used,
oxytocin is preferred. Prostaglandin E2 and E1 (misoprostol)
used for cervical ripening and postpartum hemorrhage can
theoretically cause bronchospasm. Carboprost and prostaglan-
din F2-a should be avoided [92].
On the other hand, tocolytic medications such as terbuta-
line (a b-agonist) and magnesium are actually bronchodilators
and so should actually help with asthma symptoms.
Asthma medication concentrations in breast milk are
insignificant, and such therapy should not be a contraindica-
tion to breast feeding (< 0.1% of the therapeutic dose by
weight is transferred) [93].
Conclusion
In summary, prompt diagnosis and management of asthma in
pregnancy is critical to the health of the pregnant mother and
the fetus in utero. The clinical course of asthma may get
worse in one-third of the patients when they become preg-
nant, one-third may remain stable, and in one-third of cases
 8 W. Kelly et al.
the clinical course of asthma may actually improve. Careful
monitoring of asthma during pregnancy is important. The
obstetrician in conjunction with the primary care physician or
pulmonologist (preferably) should be providing ongoing clin-
ical assessment and treatment recommendations. Poorly con-
trolled asthma can result in adverse patient and fetal
outcome. This review article is aimed to increase the aware-
ness of the need for diagnosis, monitoring, and implementa-
tion of therapy to minimize adverse outcomes.
Acknowledgments
The views expressed in this article are those of the authors
and do not reflect the official policy or position of the Depart-
ment of the Navy, Department of the Army, Department of
Defense, or the US government. The authors certify that all
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individuals who qualify as authors have been listed; that each
author has participated in the conception and design of this
work, the analysis of data (when applicable), the writing of
the document, and the approval of the submission of this
version; that the document represents valid work; that if we
used information derived from another source, the authors
have obtained all necessary approvals to use it and made
appropriate acknowledgments in the document; and that each
author takes public responsibility for it. Nothing in the presen-
tation implies any federal/DOD/DON endorsement.
For personal use only.
Declaration of interest
The authors have no relevant affiliations or financial involve-
ment with any organization or entity with a financial interest
in or financial conflict with the subject matter or materials
discussed in the manuscript. This includes employment,
consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents, received or pending, or royalties.
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