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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,
sites from leading professional organizations that are focused
and its significance is heightened when the well-being of the
on asthma education.
fetus is involved as well. The prevalence of asthma in pregnant
women has been reported in 3.7%8.4% or 200,000
Normal physiologic changes of pregnancy
376,000 women annually in the USA. About 10% of patients
have an attack during labor, and status asthmaticus has affected In a normal pregnancy, respiratory function is affected as a
0.2% of pregnancies [1,2]. As such, asthma is one of the most manifestation of hormonal changes as well as the enlarging
common medical conditions that may complicate a pregnancy uterus. With the latter, there is an elevation of the diaphragm
and the most common pulmonary disorder. Despite increased by 45 cm, which leads to a near 20% reduction in the func-
prevalence of the disease, the majority of asthmatics have tional residual capacity (FRC the volume of air that remains
uncomplicated pregnancies with no long-term manifestations. after normal exhalation) [4,5]. However, lung excursion does
However, uncontrolled asthma and its exacerbations can lead not diminish which, along with an increase in respiratory
to complications during the peripartum period and to increased rate, allows for the increase in minute ventilation associated
morbidity and mortality of the mother and fetus. With greater with pregnancy [5].
awareness, diagnosis, monitoring, and timely implementation Additionally, the decrease in FRC is offset by a smaller
of therapy, these complications can be averted significantly [3]. expansion of the chest wall cavity. Clinical manifestation of
This clinical review focuses on physiology, diagnosis, and the drop in FRC is a loss of oxygen reservoir function at the
management of asthma in pregnancy. The National Library of end of expiration. As such, rapid desaturation may occur
Medicines MEDLINE was used to conduct a search using during episodes of hypopnea or during recumbent position as
the term asthma and pregnancy. Criteria for inclusion of diaphragm elevation is at its greatest [5].
articles included data outlining respiratory physiological Signs of rhinitis, soft systolic flow murmurs or split heart
changes that are reported in pregnancy in healthy individuals sounds, prominent jugular venous pressure, and mild periph-
and in asthmatics. Additional information regarding diagnos- eral edema are common in pregnancy and are not helpful nor
tic criteria and management guidelines were taken from the are of concern [6].
recommendations of the expert panel from the National Fortunately, airway function and resistance remain mostly
Asthma Education and Prevention Program (NAEPP), Global unchanged during pregnancy. Thus, maneuvers that assess air
Strategy for Asthma Management, and American Congress of flow such as FEV1 (the volume of air exhaled during the first
Obstetrics and Gynecology websites. The literature review 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. Postgrad Med, 2015; Early Online:110

flow rate (PEFR- the maximum flow during forced expiration) severity, or limited by small size. In a 15,000 patient cohort
remain unchanged [7]. These two markers remain valuable study [12], uncontrolled asthma was associated with an
tools in diagnosing and monitoring asthma during pregnancy. increase in spontaneous abortion (odds ratio [OR] = 1.41,
A marked increase in respiratory drive and minute ventila- 95% confidence interval [CI]: 1.331.49). Murphy et al.s
tion is the most obvious physiologic change that appears to systemic reviews and meta-analyses [13,14] suggest that
increase from week 13 of gestation through week 37, and asthma is associated with preterm birth (relative risk
returns to normal by 24 weeks after delivery [5]. These [RR] = 1.41, 95% CI: 1.231.62). Other associations include
changes are thought to be a manifestation of progesterones low birth weight (RR = 1.46, 95% CI: 1.221.75), small size
effect on the respiratory center either by direct stimulation or for gestational age (RR = 1.21, 95% CI: 1.141.31), and
by increasing its sensitivity to carbon dioxide [5,8]. preeclampsia (RR = 1.54, 95% CI: 1.321.81). Patients with
This adaptive respiratory mechanism is in response to the moderate or severe asthma are more likely to have exacerba-
CO2 production which can increase by one-third to one-half tions and small or low birth weight babies. Perinatal mortality
in the last trimester. Both components of minute ventilation in the neonatal period (RR = 1.25, 95% CI: 1.051.50), but
(respiratory rate  tidal volume) are increased. Tidal volume not stillbirths (RR = 1.06, 95% CI: 0.91.25), was increased.
(the volume of air that is exchanged with normal respiration) A large observational Swedish study of nearly 37,000 pregnant
goes up by 30%35% [5]. The net result is an increase in women with reported asthma, from 1984 to 1995, was
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minute ventilation by 50%, and a subsequent respiratory compared to over 1.3 million Swedish pregnancies without
alkalosis with renal bicarbonate wasting as compensation. asthma. Maternal asthma was associated with increased rates
A typical blood gas will reveal a PaCO2 range between of preeclampsia, perinatal mortality, preterm births, and low
28 and 32 mmHg, but pH is near a normal of 7.407.45 due birth weight [15,16]. Prospective studies have failed to show
to concomitant metabolic acidosis. Knowledge of these val- an association of preterm delivery with asthma as seen with
ues is important as normalization of PaCO2 may actually the retrospective studies. However, Bracken et al. [17] did
represent CO2 retention and possible impending respiratory reveal that those with daily or moderate persistent symptoms
failure. Alternatively, chronic elevation may simply represent were at a significantly higher risk of small gestational age and
a state of uncontrolled asthma. Regardless of the cause, an preeclampsia. Dombrowski et al. [18] found only increased
increase in maternal PCO2 will affect the fetuss ability to risk of cesarean delivery rates in those with moderate-to-
For personal use only.

excrete acid and will ultimately lead to fetal acidosis [4]. severe asthma. In both studies, oral corticosteroid use was
associated with low gestation age.
Malformations (birth defects) are of particular concern
Asthma during pregnancy for expecting parents. The largest and most recent review [19]
Hormonal effects on the pathophysiology of asthma have of 56,000 pregnant patients with asthma showed an associa-
been studied, but there fails to be any consistent and convinc- tion with cleft lip with or without cleft palate infants
ing evidence for it [5]. Clinical manifestations of the disease (RR = 1.30, 95% CI: 1.011.68) and neonatal death
have been equally varied, with subjective assessment of dis- (RR = 1.49, 95% CI: 1.112.00). But there was no significant
ease having large fluctuations. Despite this, some patterns effect of asthma on major malformations (RR = 1.31, 95%
have emerged leading the NAEPP Working Group to make CI: 0.573.02) or stillbirth (RR = 1.06, 95% CI: 0.91.25).
the general conclusions that about one-third of maternal First trimester exacerbations may be associated with more
asthma cases will improve during pregnancy, one-third cases malformations (12.8 vs 7.9%, adjusted OR [aOR] = 1.48, 95%
remain unchanged, and the remainder will worsen [5]. CI: 1.042.09) [20]. Although the exact mechanisms leading
Asthma severity during past pregnancies may predict disease to these complications have not been fully delineated, hypoxe-
activity during the current pregnancy [9]. mia has been theorized as a potential contributor. Given that
The NAEPP last provided an update on management of umbilical veins have a lower PO2 than the placental venous
asthma during pregnancy in 2007 [10]. More recently, the channels, any evidence of maternal hypoxemia will lead to
American Congress of Obstetricians and Gynecologists inadequate delivery to the fetus [3,4]. Chronic hypoxemia,
(ACOG) in 2012 reaffirmed their earlier guidelines which which may be seen in uncontrolled asthma, will ultimately
largely mirrored the NAEPP recommendations [11]. All guide- lead to intrauterine growth restriction and low birth weight.
lines emphasize that the benefits of treating asthmatic pregnant Good care prevents asthma exacerbations that require oral
women outweigh any potential medication side effects, as corticosteroids, which are in turn associated with preterm
inadequate control poses a greater risk to the fetus [2,11]. 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
Complications of asthma of their asthma have better outcomes.
Is asthma associated with worse pregnancy outcomes?
Diagnosis
Yes, but patients should be reassured that the vast majority of
How do you make or confirm the diagnosis of asthma in
pregnancies end well and that appropriate management likely
a pregnant patient?
improves outcomes.
Many studies associate maternal asthma with complica- Diagnosing asthma in the pregnant patient is the same as
tions, but have been retrospective, failed to adjust for asthma for the nonpregnant patients with two important exceptions:
DOI: 10.1080/00325481.2015.1016386 Asthma in pregnancy 3

(1) Methacholine (or other bronchoprovocation testing) and pregnancy, and may occasionally have a mild eosinophilia
(2) allergen skin testing are NOT performed. with asthma [35].
The approach to diagnosis of asthma during pregnancy is Another interesting aspect of maternal asthma is that there
not dissimilar to ones approach to any nonpregnant asthmatic appears to be an association between rhinitis control and
patient. Diagnosis is based on but not limited to the combina- asthmatic symptoms, suggesting that rhinitis control during
tion of classic symptoms (wheezing, cough, chest tightness, pregnancy may help control asthma [15]. This may be diffi-
shortness of breath), temporal fluctuations (e.g. worse at cult to discriminate from the normal effects of estrogen,
night), identification of triggers (e.g. allergens, exercise), and which induces mucosal edema and hypervascularity of the
wheezing on examination (although its absence does not upper airways during pregnancy [4].
exclude a diagnosis) [2,11]. A personal history of allergies or Control of asthma is defined as minimal symptoms during
atopy (elevated immunoglobulin (Ig)E to antigens), or family day or night, no limitations with activity, lack of exacerba-
history of asthma or allergies increases the likelihood of tions, minimal use of rescue inhalers, and near-normal pulmo-
asthma in patients [22,23]. Patients should be asked about nary function tests. Thus, spirometry is not only recommended
household tobacco use, occupation, hobbies, pets, and other for the initial assessment but also recommended during
environmental exposures. A thorough and candid medication monthly assessment thereafter. Peak expiratory flow meters
history is critical as pregnant patients often stop or decrease can be helpful for monitoring of proven asthma, but are less
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medications when pregnancy is discovered [24,25]. Nonster- reliable for initial diagnosis [36]. Typical PEFR in pregnancy
oidal anti-inflammatory drugs (NSAIDs) can exacerbate should be 380550 L/min [3], but each individual needs to
asthma [26] and others such as nonselective b-blockers should establish their best effort. Maintaining levels > 90% of per-
be considered contraindicated [27]. sonal best is considered optimal control [4]. More intense
As many as one-third of patients with reported asthma ultrasound examinations may be considered at 32 weeks and
may have been misdiagnosed [28], so a careful medical beyond for those with uncontrolled disease.
records review to confirm past pulmonary function testing The remaining recommendations parallel those of the
showing reversible obstruction or inducible airway hyper general population. These include avoiding and identifying
reactivity is warranted. Wheezing over the upper airway with triggers, providing adequate education to ensure insight into
inspiratory maneuvers may suggest laryngeal dysfunction. the disease, and using a stepwise approach to pharmacologi-
For personal use only.

But note that 20% of patients can have such vocal cord issues cal therapy [4]. Similarly, the asthma severity classification
and asthma at the same time [29]. is based on the National Institutes of Health classification
Spirometry defines asthma as presence of obstruction with system [4].
a significant bronchodilator response (i.e. 12% improve-
ment in FEV1 or FVC, plus 200 cc improvement in either) Treatment of chronic asthma during pregnancy
[30]. If a significant bronchodilator response cannot be
established, it is still reasonable for a trial of therapy if the What is the recommended treatment for pregnant
remainder of clinical picture is consistent with asthma [11]. patients with chronic asthma? How is it different from
Dyspnea of pregnancy, which is described as shortness of nonpregnant patients?
breath at rest and which can occur in up to 70% of pregnan- Asthma disease management in pregnant patients is mostly
cies, is a likely progesterone-mediated phenomenon that can the same as for nonpregnant patients, with inhaled cortico-
usually be differentiated from asthma given its lack of steroids (ICSs) being the preferred long-term controller medi-
obstruction, cough or wheezing [3,31]. Pregnancy-related cation. However, (1) additional patient education efforts are
cardiomyopathy is uncommon and usually presents in the last required as medication adherence is worse; (2) some medica-
gestational month [32]. tions within a drug class are preferred because of their
Provoking airway obstruction in a patient with normal historical safety, such as the ICS budesonide; (3) stepping-
spirometry using inhaled methacholine, cold air, eucapnic down, or decreasing therapy, is usually deferred until after
voluntary hyperventilation, exercise, or other agents, is rela- delivery; (4) monitoring is more frequent (monthly); and (5)
tively contraindicated and should not be done because of the rarely, medications used around the time of delivery can
theoretical risks of causing a hypoxic asthma exacerbation. affect asthma symptoms.
Such bronchoprovocation is avoided in pregnant patients to
avoid the potential of increased bronchospasm and clinical
Education
decompensation and providers may opt for empiric therapy
instead [3]. Skin testing for allergens is generally contraindi- During pregnancy, patients are less likely to take their
cated because potent antigens may trigger anaphylaxis and medications and physicians are less likely to prescribe them.
endanger the mother and fetus [33]. Serum RAST testing for Perhaps due to concerns about side effects, pregnant patients
IgE levels on suspected allergens such as dust mites, animal with asthma have lower adherence to medications [24]. From
dander, pollens, and cockroach can be obtained if desired. pharmacy data [25] of 2000 pregnant patients, asthma pre-
Chest X-rays are not indicated for proven asthma respond- scriptions were less likely to be filled during the first trimester
ing to therapy in any patient, pregnant or not [34], but they than during the 3 months prior to pregnancy, with 38% not
can be obtained if an alternative diagnosis is suspected. being on any medications. Reasons for pregnant patients to
Serum complete blood count, if ordered, may show decrease or discontinue medications without discussing with
anemia due to fluid volume shifts or iron deficiency in their doctors include lack of support and information about
4 W. Kelly et al. Postgrad Med, 2015; Early Online:110

what to do, concerns about the safety of the medications, past such as air filtration or special bed covers (animal dander,
experiences, and desire for an all natural pregnancy [37]. In dust mite, mold, cockroach) [45].
one study, pregnant women mistakenly perceived a 42% tera-
togenic risk with oral corticosteroids, 12% risk with ICSs, and
Exercise triggers
a 5% risk with short-acting b-agonists (SABAs) [38]. Accord-
ingly, another prescription claims data cohort of With exercise-induced symptoms, inhaled SABAs 30 minutes
112,171 patients showed decreased asthma medication use prior along with a warm-up routine may reduce the degree of
from 5 to 13 weeks of pregnancy. It was 23% lower for ICSs, bronchospasm [46]. A mask or scarf over the mouth may
13% lower for SABAs, and 54% lower for rescue help with exercise bronchospasm in cold weather [47].
corticosteroids [15].
Empowering patients is important, since positive beliefs
Nutrition
about asthma, low anxiety, and a perception of good asthma
control have been associated with less exacerbations Obesity while pregnant has been linked to adverse offspring
(OR = 0.92, 95% CI: 0.850.98) for preterm birth outcomes including metabolic syndrome, behavioral prob-
(OR = 0.84, 95% CI: 0.750.94), C-section without labor lems, and asthma [48]. Obese patients are more likely to have
(OR = 0.84, 95% CI: 0.720.97) [38]. asthma exacerbations (OR = 1.3, 95% CI: 1.11.7), undergo
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Although regular home monitoring of lung function with C-section (OR = 1.6, 95% CI: 1.33.0), have preeclampsia/
peak flow meters may be challenging and cumbersome for gestational hypertension (OR = 1.7, 95% CI: 1.32.3) and
some, it should be included as part of a comprehensive gestational diabetes (OR = 4.2, 95% CI: 2.86.3) [49].
asthma action plan [39]. The following websites are available
for patient education regarding asthma management.
Pharmacologic therapy: recommendations
http://www.acaai.org/allergist/liv_man/pregnancy/Pages/
and safety
default.aspx
http://www.aafa.org/display.cfm?id=8&sub=17&cont=177 The Global Initiative for Asthma stated that pregnant
http://www.nhlbi.nih.gov/health/public/lung/index. women with asthma should be advised that poorly controlled
htm#asthma asthma and exacerbations provide a much greater risk to their
For personal use only.

baby than do current asthma treatments [50]. Medications


are never tested on pregnant patients, and most asthma
Tobacco cessation
medications have an US Food and Drug Administration
Active smoking is associated with an increased risk of (FDA) drug classification of C (risk cannot be ruled out)
daytime and nighttime asthma symptoms and fetal growth because there are no controlled studies in pregnant women.
abnormalities (small size and lower birth weight) [40]. Patients should be fully informed but can be legitimately
Additionally second-hand smoke during pregnancy is associ- reassured that decades of numerous studies support medica-
ated with subsequent asthma in the child even if the mother tion safety.
herself does not smoke (RR = 1.34, 95% CI: 1.011.76) [41]. The medication recommendations that follow are consis-
Smoking increases the risk of intensive care unit (ICU) tent with latest guidelines including NAEPP, National Heart,
admission with influenza-like illnesses (RR = 2.77, 95% CI: Lung, and Blood Institute Expert Panel Report 3 from 2007
1.196.45) [42]. [10] (Figure 1), British Thoracic Society/Scottish 2012 [51],
and American Congress of Obstetrics and Gynecology
(ACOG) 2012 reaffirmation of their 2008 guidelines [11].
Infection avoidance and vaccination
Treatment is based on disease control and severity, such as
Viral upper respiratory infections (URIs) are the leading worse pulmonary function (lower FEV1) and more frequent
cause of asthma exacerbations in pregnant women. This was symptoms disrupting daytime function or sleep or requiring
evidenced in a prospective cohort study [43] of pregnant rescue medication use leading to more (or higher dosages of)
women whose self reported symptoms were confirmed medications. Whereas in nonpregnant patients, the use of
with polymerase chain reaction (PCR) swabs. The results SABA at 20-minute intervals three times during acute exacer-
suggested an increased susceptibility to these infections (inci- bation is recommended (Figure 1), pregnant women may
dent rate ratio = 1.77, 95% CI: 1.302.42) as 71% developed need to seek medical attention sooner. Asthma is not well
a URI during their pregnancy, resulting in poorer asthma con- controlled and requires more aggressive treatment with any
trol/exacerbation in two-thirds, with increased likelihood of of the following: (1) symptoms are more frequent than 2 days
pre-eclampsia. Furthermore, pregnant women have been per week, (2) nighttime awakenings occur more than twice
identified as an at risk population to influenza, including per month, (3) there is interference with normal activity,
H1N1, and routine flu vaccination is recommended [44]. (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
Allergen avoidance
achieved, with consideration for jumping ahead two steps if
It is pertinent to avoid triggers (irritants, certain foods, medi- there are significant symptoms.
cations like NSAIDs), modify routines (limiting cold, dry air), Step 1: SABA albuterol metered-dose inhaler (90 mg/puff)
and attempt specific environmental controls, when available, 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. birth weight, small gestational age, or major congenital
Nebulizers offer no advantage [52]. A dose can also be taken malformations found no associations with b-agonist use. Sys-
30 minutes before exercise. The need for this rescue inhaler tematic reviews of 190 exposures and casecontrol data from
use (from 0 to up to > 3 times/day) intuitively measures 156 exposed infants showed no increased risk of congenital
asthma control and is formally part of the Asthma Control malformations, preterm delivery, or preeclampsia. Long-
Test (ACT). acting b-agonists (LABAs) should always be used in
Safety: A study of 259 prospectively studied patients conjunction with an ICS, ideally as a combination product.
showed no adverse outcomes in nine categories [53]. In a Available agents include salmeterol and formoterol [51], with
Canadian cohort study of 13,117 pregnancies, there was no salmeterol preferred due to longer history of use.
association between first trimester SABA use and any of the When SABAs are required more than twice per week, step
1242 malformations noted (aORs = 1.04, 95% CI: 0.921.17) up to a daily controller medication is required. Dose ranges
[54]. Studies that have shown an association with adverse are provided below, but the most important outcome is clinical
outcomes have often not accounted for asthma disease response to therapy.
severity. These include the National Birth Defects Prevention Step 2: ICSs at low dose budesonide initial: 360 mg
Study casecontrol data [55] from mothers of 2711 infants twice daily (or any equivalent ICS). Budesonide dose range
with orofacial clefts and 6482 mothers of live-born infants is 180600 mg/day in divided doses. Note that there are
without birth defects, delivered between 1997 and 2005. different brands and also the dose of dry powder inhalers
Albuterol use during the periconceptional period was asso- (DPIs) is often a little higher than metered-dose inhalers
ciated with cleft lip (aOR = 1.79, 95% CI: 1.072.99) and (hydrofluoroalkane [HFA]). Equivalent fluticasone HFA dose
cleft palate (aOR = 1.65, 95% CI: 1.062.58). Similarly, is 88264mg/day. The best long-term controller medication
Lin et al. have reported a small increase in congenital heart is ICSs. By reducing inflammation, they improve symptoms,
defects in one small casecontrol study (n = 22, OR = 2.20, decrease disease flares, and increase pulmonary function. In
95% CI: 1.054.61) [56] and an association with gastroschi- pregnant patients specifically, ICS has been shown to reduce
sis in a larger series (OR = 2.06, 95% CI: 1.193.59) [57]. acute asthma attacks and reduce the risk of readmission fol-
However, another casecontrol study [58] looking at low lowing an exacerbation [59,60]. Budesonide has more gesta-
birth weight, and a 1828 patient cohort study [59] of low tional safety data available, earning it an FDA pregnancy
6 W. Kelly et al. Postgrad Med, 2015; Early Online:110

category B. There is no expectation or evidence that other with formoterol. Low-dose ICSs with LTRA or low-dose
ICSs would not behave similarly. ICSs with theophylline are also guideline-acceptable.
Safety: Concern for side effects of inhaled medications Step 4: Medium-dose ICSs. Budesonide > 6001200 mg/
and, in particular, ICSs has been explored as well, given that day or equivalent (i.e. fluticasone HFA 264540 mg/day) plus
ICSs are the preferred medication for management of asthma. LABA. In the USA, combination agents include Advair
A Swedish registry provides some reassuring data [61], (fluticasone plus salmeterol) and Symbicort (budesonide plus
including 2968 mothers who reported the use of inhaled formoterol). Again, medium-dose ICSs with an LTRA or
budesonide during early pregnancy and gave birth to infants theophylline are listed as alternative controller options.
of normal gestational age, birth weight, and length, with no Step 5: High-dose ICS plus LABA. This is budesonide
increased rate of stillbirths or multiple births. Data from > 1200 mg/day or equivalent (i.e. fluticasone HFA > 440
the Danish national Birth Cohort [62,63] is also reassuring 800 mg/day) plus a LABA.
in terms of infant outcomes. Authors looked for 17 diseases Step 6: Step 5 treatment plus oral systemic glucocorti-
in the children of 4000 pregnant asthmatics out to a median coids. Prednisone, prednisolone, and methylprednisolone
age of 6.2 years. The only finding was of endocrine, cross the placenta at very low concentration, whereas dexa-
metabolic, and nutritional disorders (hazard ratio = 1.84, methasone and betamethasone reach the fetus at higher con-
95% CI: 1.132.99). Interestingly, there has effectively been centration. Dose is lowest needed for the shortest amount
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a randomized trial of budesonide with 319 pregnancies occur- of time but consider 40 mg/day prednisone for 514 days.
ring during a larger trial of 7243 asthma patients, with no Safety: Cohort studies by Schatz et al. show an association
increase in adverse pregnancy outcomes seen [64]. of oral corticosteroids and preeclampsia in multivariate analy-
However, high-dose ICSs have raised some safety ses (n = 824, OR = 2.0, p = 0.027) [73]. Others show
concerns. In a Blais cohort study [65], 13,280 significant dif- increased risk of gestational diabetes (12.9 vs 1.5%) and
ferences in malformations were found with high- versus C-section (38.7 vs 19.2) [74]. For the infants, there is
Low-dose ICS (aOR = 1.63, 95% CI: 1.022.60). Addition- increased risk of preterm birth (n = 2123, OR = 1.54, 95%
ally a Canadian cohort study of low birth weight, preterm CI: 1.022.33) and birth weight < 2500 g (OR = 1.80, 95%
birth, and small for gestational age found no association with CI: 1.132.88) [59], including adjustments for asthma
low-dose ICS and a nonsignificant increasing trend with severity. Large reviews support these gestational growth find-
For personal use only.

doses equivalent to > 200 mg/day budesonide [66]. In con- ings, including studies of corticosteroids given for indications
trast, a population data from 52,000 patients taking steroids other than asthma [75]. Cleft lip and palate with steroids has
(in any form) out of 830,000 pregnancies did not show an been a concern in animal studies, and a 2000 analysis [76] of
association with cleft lip or cleft palates [67,68]. Several stud- casecontrol studies suggested an association (OR = 3.35,
ies failed to show an increased risk of malformations with 95% CI: 1.975.69). However, analysis of cohort studies by
ICS use, and in fact, it has been shown that the risk of low the same authors did not show this trend. Furthermore, in a
birth weight can be significantly higher in those not on ICS Danish cohort from 1999-2009, only one (0.08%) out of
[4,15,18,69]. Thus, one can reasonably conclude that the risk 1449 primiparous women on inhaled or oral steroids resulted
of uncontrolled disease far outweighs any potential risks of in an oral birth defect [77]. The same authors reviewed pub-
standard medical therapy. lished studies to date and RR estimates ranging from
As far as alternative controller medications, they are 0.8 (95% CI: 0.41.7) to 2.1 (95% CI: 0.59.6) overall and
available but not recommended if ICSs can be tolerated. In a ORs from 0.6 (95% CI: 0.21.7) to 5.2 (95% CI: 1.517.1)
randomized control trial ICSs (beclomethasone) for oral clefts, all insignificant [77].
versus theophylline, there was no difference in maternal Starting immunotherapy during pregnancy is contraindi-
or fetal outcomes, but the beclomethasone was better toler- cated because the risk of anaphylaxis is unknown and the
ated [60]. Theophylline also requires frequent drug level benefits appear minimal [78]. However, women already
monitoring [70]. receiving allergy shots, on a stable and non-escalating dose,
Based on one randomized but small study [71] (n = 96), and who appear to be benefiting from them, can continue
leukotriene receptor antagonists (LTRAs) were not associated safely based on retrospective patient series [79]. Interestingly,
with an increased risk of pregnancy loss, gestational diabetes, this has also been shown to be true for sublingual immuno-
preeclampsia, low maternal weight gain, preterm delivery, therapy [80].
low Apgar scores, or reduced measures of birth length and Omalizumab (Xolair), a recombinant DNA-derived mono-
head circumference in infants. But there was a slight clonal antibody that selectively binds to human IgE, has been
decrease in birth weight, and birth defects were increased shown to be helpful for non-pregnant, symptomatic asthmatic
compared to controls without asthma. patients refractory to standard therapy, but with underlying
Step 3: Medium-dose ICSs. Budesonide > 6001200 perennial allergies and elevated serum IgE (Steps 5 and 6). It
mg/day or equivalent (i.e. fluticasone HFA 264440 mg/day). is FDA pregnancy category B, and preliminary data from the
Asthma guidelines do say or low-dose ICS plus long-acting industry-sponsored pregnancy registry (EXPECT study) from
b agonist (LABA). Of note LABA monotherapy, without 170 pregnancies are reassuring, but this has not yet been pub-
ICS, is contraindicated because of concerns over increased lished. Anaphylaxis is a small but persistent risk (estimated
serious and fatal adverse events [72]. LABA salmeterol is pre- 0.2%), and its weight-based dosing may be challenging given
ferred the US given longer duration of clinical use compared changes during pregnancy [81].
DOI: 10.1080/00325481.2015.1016386 Asthma in pregnancy 7

Monitoring magnesium has been shown to increase lung function and


decrease admissions in children [88].
Monitoring of asthma should be at least monthly for stable
Admission to the hospital is required if there is a persistent
disease, and in conjunction with obstetric providers routine
oxygen requirement, PEFR < 70%, fetal distress, mental
assessment of intra-uterine growth. Clinical assessment should
status changes, normal or elevated PCO2, slow response to
include symptom frequency, quality of life, and rescue inhaler
medical therapy, or other clinical concerns. Given higher risk
medication use and technique, peak flow measurements
of hypoxemia (as manifestation of decreased FRC) [89], and
(if done), and lifestyle modifications, rescue inhaler can
laryngeal edema which may complicate intubation (especially
include checklists or quantification, such as the ACT, which
if pre-eclampsia) [90], pregnant patients with asthma exacer-
may be useful for confirming controlled asthma [82,83].
bation should be admitted to a monitored setting such as an
Measurement of Fractional Exhaled Nitric Oxide (FENO) is a
intensive care unit (ICU). Although pregnant patients with
non-invasive and often well tolerated procedure, which may
asthma are just as likely to be admitted as those that are
correlate with airway inflammation. Although not routinely
nonpregnant (24% vs 21%, p = 0.61), they are less likely to
used or available, it may at times serve as an adjunct to
be given systemic steroids in the emergency department
adjusting therapy in asthmatics. In a study of 220 pregnant
(66% vs 44%, p = 0.002) or discharged with them (38% vs
patients [84], FENO-based titration as compared to using clini-
64%, p = 0.002). One can assume this discrepancy is for
Postgraduate Medicine Downloaded from informahealthcare.com by Kainan University on 04/23/15

cal symptom alone resulted in fewer exacerbations (0.288 vs


fear of medication toxicity, but inadequate treatment has been
0.615 per pregnancy), improved quality of life scores, and
shown to lead to a near 3 fold increase in prolonged symp-
decreased neonatal admissions (8% vs 17%, p = 0.046).
toms (95% CI:1.26.8) [91]. Corticosteroid treatment for
Stepping-down of therapy is usually done postpartum to
3 to 10 days and outpatient follow up of 5 days, if dis-
avoid precipitating problems. An exception may be those
charged, has been recommended.
patients doing very well can step down from level 5 or level 6.

Peripartum asthma care and concerns


Acute exacerbations
Fortunately, 90% of pregnant patients have no symptoms dur-
Acute asthma exacerbations can be especially distressing for ing delivery and those who do may only require inhaled
For personal use only.

both patients and their medical providers. Undertreatment bronchodilators [9]. Adequate hydration is standard care as is
must be avoided. continuing the patients usual asthma medications. When pro-
A literature review of asthmatic pregnant patients viding analgesia, NSAIDs can cause problems if the patient
hospitalized for exacerbation, identified an overall incidence is aspirin-sensitive. Morphine can also cause histamine
rate of 6%, with the majority attributed to severe/difficult to release, an effect not seen with fentanyl. C-section rates for
control asthma, viral infections, and non-adherence to asthma patients are increased [51], and conversely patients
medications [85]. Risk of severe exacerbations in patients with C-section may have an increased risk of postpartum
with mild, moderate, and severe asthma is reported as 8%, asthma exacerbation. For surgery, epidural anesthesia may
47%, and 65%, respectively [86]. In that report, mean have benefits over intubation as in nonpregnant patients.
gestational age at presentation was 25.1 9 weeks. Patient on chronic or frequent steroids may be at risk of adre-
Like with all those with asthmatic exacerbations, therapy nal insufficiency which can be prevented with stress dosing
will include close monitoring with supplemental oxygen, (50 mg hydrocortisone every 6 hours) during labor and for
inhaled beta agonists (inhaled anti-cholinergics may be added the first postpartum day.
as an adjunct), and possibly systemic steroids. Differences in If medical therapy for postpartum hemorrhage is used,
management include a higher goal oxygen saturation for the oxytocin is preferred. Prostaglandin E2 and E1 (misoprostol)
pregnant woman (95% has been suggested) [86,87] and addi- used for cervical ripening and postpartum hemorrhage can
tion of continuous fetal monitoring. theoretically cause bronchospasm. Carboprost and prostaglan-
If an arterial blood gas is obtained, it is important to note din F2-a should be avoided [92].
that a normal carbon dioxide level may suggest impending On the other hand, tocolytic medications such as terbuta-
respiratory failure, as pregnant patients normally have line (a b-agonist) and magnesium are actually bronchodilators
hypocapnia and respiratory alkalosis due to increased minute and so should actually help with asthma symptoms.
ventilation [88]. Asthma medication concentrations in breast milk are
Chest radiographic imaging is not contraindicated but not insignificant, and such therapy should not be a contraindica-
routinely recommended unless an alternative diagnosis is tion to breast feeding (< 0.1% of the therapeutic dose by
considered. If venous thromboembolism is suspected, con- weight is transferred) [93].
sider leg ultrasound or ventilationperfusion scan instead of
computed tomography angiogram in order to reduce radiation
Conclusion
risks.
Intravenous aminophylline has been shown to have no In summary, prompt diagnosis and management of asthma in
advantage over continuous ICS and does not decrease hospi- pregnancy is critical to the health of the pregnant mother and
tal stays, and ICS (along with b-agonists and oral steroids) the fetus in utero. The clinical course of asthma may get
does decrease readmission rates (33% vs 12%, p < 0.05, worse in one-third of the patients when they become preg-
OR = 3.63, 95% CI: 1.0113.08) [87]. Intravenous nant, one-third may remain stable, and in one-third of cases
8 W. Kelly et al. Postgrad Med, 2015; Early Online:110

the clinical course of asthma may actually improve. Careful [10] National Asthma Education and Prevention Program. Session 4.
Expert panel report III: Guidelines for the diagnosis and manage-
monitoring of asthma during pregnancy is important. The
ment of asthma. Bethesda, MD: National Heart, Lung, and Blood
obstetrician in conjunction with the primary care physician or Institute; 2007; NIH publication no. 08-4051.
pulmonologist (preferably) should be providing ongoing clin- [11] Dombrowski MP, Schatz M; ACOG Committee on Practice Bulle-
ical assessment and treatment recommendations. Poorly con- tins-Obstetrics. ACOG practice bulletin: clinical management
guidelines for obstetrician-gynecologists number 90, February
trolled asthma can result in adverse patient and fetal 2008: asthma in pregnancy. Obstet Gynecol 2008;111:45764.
outcome. This review article is aimed to increase the aware- [12] Blais L, Kettani FZ, Forget A. Relationship between maternal
ness of the need for diagnosis, monitoring, and implementa- asthma, its severity and control and abortion. Hum Reprod 2013;
tion of therapy to minimize adverse outcomes. 28:90815.
[13] Murphy VE, Schatz M. Asthma in pregnancy: a hit for two. Eur
Respir Rev 2014;23:648.
[14] Murphy VE, Wang G, Namazy JA, et al. The risk of congenital
Acknowledgments malformations, perinatal mortality and neonatal hospitalization
The views expressed in this article are those of the authors among pregnant women with asthma: a systematic review and
meta-analysis. BJOG 2013;120:81222.
and do not reflect the official policy or position of the Depart- [15] Namazy JA, Schatz M. Current opinion in pulmonary medicine.
ment of the Navy, Department of the Army, Department of 2005;11:5660.
Defense, or the US government. The authors certify that all [16] Kllen B, Rydhstroem H, Aberg A. Asthma during pregnancy a
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individuals who qualify as authors have been listed; that each population based study. Eur J Epidemio 2000;16:16771.
[17] Bracken MD, et al. Asthma Symptoms, Severity and Drug Ther-
author has participated in the conception and design of this apy: A Prospective Study of Effects on 2205 Pregnancies. Obstret
work, the analysis of data (when applicable), the writing of Gynecol 2003;102:73952.
the document, and the approval of the submission of this [18] Dombrowski M, Schatz M, et al. Asthma During Pregnancy. Obstet
Gynecol 2004;103:512.
version; that the document represents valid work; that if we
[19] Murphy VE, Wang G, Namazy JA, et al. The risk of congenital
used information derived from another source, the authors malformations, perinatal mortality and neonatal hospitalization
have obtained all necessary approvals to use it and made among pregnant women with asthma: a systematic review and
appropriate acknowledgments in the document; and that each meta-analysis. BJOG 2013;120:81222; Review. Erratum in:
BJOG. 2014;121(5):652.
author takes public responsibility for it. Nothing in the presen- [20] Blais L, Forget A. Asthma exacerbations during the first trimester
tation implies any federal/DOD/DON endorsement. of pregnancy and the risk of congenital malformations among
For personal use only.

asthmatic women. J Allergy Clin Immunol 2008;121:137984;


Declaration of interest 1384.e1.
[21] Namazy JA, Murphy VE, Powell H, et al. Effects of asthma
The authors have no relevant affiliations or financial involve- severity, exacerbations and oral corticosteroids on perinatal out-
comes. Eur Respir J 2013;41:108290; Review.
ment with any organization or entity with a financial interest
[22] Arbes SJ Jr, Gergen PJ, Vaughn B, Zeldin DC. Asthma cases attrib-
in or financial conflict with the subject matter or materials utable to atopy: results from the Third National Health and
discussed in the manuscript. This includes employment, Nutrition Examination Survey. J Allergy Clin Immunol 2007;120:
consultancies, honoraria, stock ownership or options, expert 113945.
[23] Platts-Mills TA. How environment affects patients with allergic dis-
testimony, grants or patents, received or pending, or royalties. ease: indoor allergens and asthma. Ann Allergy 1994;72:3814;
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