Review
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CONTENTS
Risks of asthma
in pregnancy
Treatment of asthma
in pregnancy
New NIH guidelines in
management of asthma
in pregnancy
Quality of care & outcomes
in pregnancy in patients
with asthma
Summary & conclusions
Expert commentary
& five-year view
Key issues
References
Affiliations
†
Author for correspondence
University of Tennessee Center for
the Health Sciences, College of
Medicine, 50 North Dunlap Street,
4th Floor ,West Patient Tower
Memphis, TN 38103, USA
Tel.: +1 901 572 5377
Fax: +1 901 572 4478
mstreck@utmem.edu
KEYWORDS:
asthma, cromolyn sodium,
guidelines, inhaled
corticosteroids, leukotriene
modifiers, long-acting β agonists,
nedocromil sodium,
omalizumab, outcomes,
pregnancy, quality of care,
short-acting β agonists, systemic
corticosteroids, theophylline
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Quality of care of asthma
during pregnancy
Maria R Streck† and Michael S Blaiss
The goal of asthma management during pregnancy is to keep the mother symptom free
and to prevent complications in the fetus. Asthma is a common chronic condition in
pregnancy that, if inadequately treated, has the potential to cause adverse effects for both
mother and fetus. Aggressive treatment during pregnancy can decrease costs associated
with asthma now and additional costs later if the fetus has a poor outcome due to maternal
asthma. A stepwise approach to the management of asthma during pregnancy has been
developed and is not unlike the management of the nonpregnant patient. Although there
are no double-blind, placebo-controlled studies on asthma medications in pregnant
women, large cohort studies have shown the efficacy of aggressive management. With
adequate control of asthma from the preconception time through delivery, studies have
shown similar outcomes in asthmatic patients compared with nonasthmatics, thus obtaining
the goal of a symptom-free mother and a healthy baby.
Expert Rev. Pharmacoeconomics Outcomes Res. 6(1), 67–77 (2006)
Asthma is a chronic inflammatory disease of asthma severity class, with worse symptoms
the airways that affects 3.8–8.4% of pregnant related to more severe disease [6]. Most asth-
women [1], making it one of the most common matic patients have the same degree of asthma
chronic conditions of pregnancy. Importantly, severity in future pregnancies as in their first
the prevalence of asthma appears to be increas- pregnancy [7]. It is also known that the level of
ing [1]. Based on the need for improved care for asthma symptoms during pregnancy tends to
the pregnant asthmatic patient, in 1993 the parallel that of rhinitis symptoms [8]. Asthma
National Asthma Education and Prevention exacerbations most commonly occur between
Program (NAEPP) Working Group on the 24th and 36th week of gestation with a
Asthma and Pregnancy released a report enti- paucity of symptoms during the last 4 weeks of
tled The Management of Asthma during pregnancy and during labor and delivery.
Pregnancy [2]. This report reviewed the infor- Within 3 months of delivery, almost 75% of
mation available regarding the inter-relation- women return to their prepregnancy status [9].
ships between asthma and pregnancy and pro- This data obviates the need for good control of
vided recommendations for the management maternal asthma during pregnancy, which is
of asthma during pregnancy [3]. A stepwise important for the wellbeing of both the
approach to the pharmacologic treatment of mother and her baby.
asthma in pregnancy was outlined and, based
on a systematic review of the literature, was Risks of asthma in pregnancy
revised in 1997 [4] and 2002 [5]. On the basis Aggressive treatment for maternal asthma is
of the NAEPP criteria, a large cohort study necessary because poor control can lead to dev-
found that asthma severity increased in 30% astating outcomes in both the mother and the
and decreased in 23% of women from the fetus. This can lead to high costs now due to
beginning to the end of pregnancy [6]. This hospitalizations and emergency department
study also showed that gestational asthma visits, and continued medical costs due to
morbidity was directly related to the initial complications in the infant over time. An
10.1586/14737167.6.1.67 © 2006 Future Drugs Ltd ISSN 1473-7167 67
Streck & Blaiss
understanding of the physiologic changes of the respiratory sys-
tem during pregnancy helps to appreciate the importance of
asthma control for optimal maternal and fetal outcomes. It is
likely that the resting minute ventilation increases during preg-
nancy are attributable to the central respiratory stimulant effect
of progesterone [10]. The sensation of dyspnea in pregnancy,
referred to as physiologic dyspnea, is related to the increase in
minute ventilation. A respiratory alkalosis occurs as minute
ventilation increases, with the normal partial pressure of carbon
dioxide (PaCO2) falling from 40 to 34 mmHg. There is a par-
tial compensation for the respiratory alkalosis as the kidney
excretes increased bicarbonate. The major change in lung vol-
ume during pregnancy is a decrease in the functional residual
capacity related to the increase in uterus size. The airway
mechanics remain unchanged. Pregnancy has no effect on
forced expiratory volume in 1 second (FEV1), forced vital
capacity (FVC) or forced expiratory flow (FEF) [11]. Thus, a
decrease in FEV1/FVC should be considered related to
obstructive lung disease, just as in the nonpregnant patient [7].
Maintaining adequate fetal oxygenation is of utmost impor-
tance in caring for the pregnant asthmatic. The placenta acts as a
simple concurrent oxygen exchanger and, thus, the fetal umbili-
cal vein partial pressure of oxygen (PO2) can never exceed mater-
nal venous PO2 [12]. The fetus is able to tolerate the low concen-
tration of oxygen by several adaptive measures, including
increased affinity for oxygen by fetal hemoglobin and higher
fetal hemoglobin levels that increase the oxygen-carrying capac-
ity of the blood [13]. Despite these adaptive measures, even small
decreases in maternal arterial PO2 seen with acute asthma
episodes can lead to a significant decrease in fetal oxygenation [7].
Maternal asthma is associated with adverse outcomes for
both the infant and mother. The incidence of preterm labor,
low-birth-weight pregnancies, pre-eclampsia and congenital
anomaly are increased in asthmatic women [14]. Severe, persist-
ent asthma has been related to the development of maternal
hypertension, pre-eclampsia, placenta previa, uterine hemor-
rhage and oligohydramnios [9]. Patients whose asthma is poorly
controlled during pregnancy are at increased risk of cesarean
delivery [15]. Inadequate asthma control is also associated with
premature birth, low birth weight and stillbirth [12,16]. How-
ever, a smaller prospective study that involved close observation
of the subjects and care by physicians with expertise in asthma
showed that pregnancy outcome is similar in asthmatic and
nonasthmatic women [17]. It is likely that the overall wellbeing
of the fetus is dependent on the severity of asthma [18]. Fetal
birth weight, a global index of fetal growth and development,
correlates with the mother’s FEV1 [19]. Women with the lowest
percent predicted FEV1 tended to have babies of the lowest
birth weights. This emphasizes the need for aggressive control
of maternal asthma for the wellbeing of the fetus.
Treatment of asthma in pregnancy
The principles of management of asthma during pregnancy are
similar to those recommended for nonpregnant women [2,20].
The goals of asthma management during pregnancy include:
68
optimal control of asthma symptoms, attainment of normal
pulmonary function, prevention and reversal of asthma exacer-
bation and prevention of maternal and fetal complications [21].
With regard to treatment, the cornerstone for all patients with
asthma includes environmental control, pharmacologic treat-
ment and allergen immunotherapy [22]. It is even more impor-
tant to lessen exposures to triggers during pregnancy because
this may help decrease the need for medications and prevent
exacerbations that are harmful to the mother and fetus [22].
Education on proper allergen avoidance can lead to improved
asthma control during pregnancy.
Despite aggressive environmental control measures, most
women require some form of pharmacotherapy for asthma dur-
ing pregnancy. There is limited information available on the
long-term efficacy and safety of approved asthma medications
in pregnancy because double-blind, placebo-controlled trials
can not be ethically performed in pregnant women. Epidemio-
logical data from population studies and length of time the
agent has been available for use have been the criteria for rec-
ommendations for medications during pregnancy [22]. Accord-
ing to the FDA, no asthma medications can be considered safe
during pregnancy. Because there are few safety studies on medi-
cations during pregnancy, the FDA has developed categories for
drugs (A, B, C, D and X) [23]. Category A is given to medica-
tions in which controlled studies in women failed to show a
danger to the fetus in the first trimester. Category B is given to
agents in which animal studies have not shown fetal danger but
there are no controlled studies in humans. Category C is given
to agents in which adverse fetal effects have been described in
animals and no controlled studies in women or no studies in
animals are available. Category D is given to medications for
which there is clear data showing risk to the fetus, but the ben-
efits from use in pregnancy may be acceptable despite the risks.
Category X is used for drugs that can cause fetal abnormalities,
as indicated in animal and human studies, and should never be
used in women who are or may become pregnant [22]. The
NAEPP published a set of recommendations in 2004 to guide
in the pharmacologic treatment of the pregnant patient [20]. As
outlined in the next section, a stepwise approach is
recommended for optimal control of asthma during pregnancy.
Allergen immunotherapy also has a role in treatment of the
pregnant asthmatic patient. It is an important disease-modify-
ing treatment that has been shown to decrease symptomatology
and need for medications in asthma. It is considered safe and
effective for the pregnant woman and can be continued during
pregnancy [24,25]. Allergen immunotherapy should not be
started during pregnancy [7] and, because of the possible risk of
an anaphylactic reaction, the strength of the allergen extract
should not be increased during pregnancy [22].
Concerns regarding potential adverse or teratogenic effects of
asthma medications in pregnancy may lead to poor compliance
with treatment [26]. The NAEPP Working Group on Asthma
and Pregnancy issued recommendations in 1993 that stressed
aggressive asthma treatment in pregnant women and advocated
daily controller medication for those with persistent asthma [2].
Expert Rev. Pharmacoeconomics Outcomes Res. 6(1), (2006)

As was shown by Schatz and colleagues, adequately controlled
asthma is associated with outcomes not significantly different
from the nonasthmatic population [27]. Outlined below are the
pharmacologic treatment options during pregnancy.
Short-acting β-agonists
Short-acting β2-agonists are the preferred treatment for mild
intermittent asthma and for acute exacerbations in all asthmatic
patients. A prospective study of asthma during pregnancy did
not associate the use of β-agonists with an increased risk of con-
genital malformations or other adverse pregnancy outcomes [28].
Use of oral and parenteral β2-agonists should be avoided
because of lack of safety data, the increased risk of side effects
and the potential to inhibit delivery [29]. They are labeled FDA
category C for pregnancy.
Inhaled corticosteroids
Inhaled corticosteroids (ICS) are the cornerstone of therapy
and, because of their anti-inflammatory action, are the most
effective class of asthma-controller medications [4,5]. Studies
have demonstrated that ICS reduce the risk of an acute asthma
exacerbation when used throughout pregnancy [30], and reduce
the rate of asthma-related readmissions to the hospital for preg-
nant women when used after discharge from the hospital [31].
Published data are supportive for beclomethasone and budeso-
nide during pregnancy. In the Michigan Medicaid study, moth-
ers who were exposed to beclomethasone during the first tri-
mester showed no evidence of association between ICS and
congenital defects [32]. In data analyzed from the Swedish Med-
ical Birth Register, Norjavaara and de Verdier found that the
mothers who reported use of inhaled budesonide during early
pregnancy gave birth to infants of normal gestational age, birth
weight and length, with no increased rate of stillbirths or multi-
ple births [33]. Because of this study, budesonide is labeled FDA
category B for pregnancy, while the other ICS remain category
C. Recent data by Namazy and colleagues suggest that the use
of ICS by pregnant asthmatic women does not reduce intra-
uterine growth and supports the use of ICS in the management
of persistent asthma during pregnancy [34]. Newer ICS are now
available but data are lacking on safety during pregnancy. In
regards to this, the April 2000 position statement developed by
a joint committee of the American College of Obstetrics and
Gynecology and the American College of Allergy, Asthma and
Immunology says, ‘it would not be unreasonable to continue a
different (from beclomethasone or budesonide) inhaled corti-
costeroid in a patient well-controlled by that drug (fluticasone
or other newer agents) prior to pregnancy.’ [35]
Cromolyn sodium & nedocromil sodium
These medications have an anti-inflammatory effect by stabiliz-
ing the mast cell. There are long-term safety data with inhaled
cromolyn that show it is a reasonable option for women during
pregnancy [36]. The Michigan Medicaid study showed no
increase in the expected number of birth defects in women tak-
ing cromolyn during the first trimester of pregnancy [32]. This
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Quality of care of asthma during pregnancy
was supported by the Kaiser-Permanente study, which showed
no increase in the incidence of major congenital malformations
in patients exposed to cromolyn [28]. In a study by Bracken and
colleagues, there was no increased risk of preterm delivery
among women who received cromolyn during pregnancy [37].
There are no published human gestational studies of inhaled
nedocromil. Because of the above data, these medications are
labeled FDA category B.
Leukotriene modifiers
Three leukotriene modifiers, including the 5-lipoxygenase
inhibitor zileuton and the leukotriene receptor antagonists,
montelukast and zafirlukast, are currently approved for the
treatment of asthma. To date, there are no human teratogenic
effects seen with these agents [38]. In a small study of nine
women by Bracken and colleagues, there was no reported
increased risk of preterm delivery caused by leukotriene
modifiers [37]. They are labeled FDA category B.
Theophylline
Although theophylline has been available for over 50 years and
has been shown to lack teratogenic effects during pregnancy, its
use has drastically decreased due to its possible toxicity with ele-
vated serum levels and the introduction of newer, safer medica-
tions [28]. In a comparison with inhaled beclomethasone, oral
theophylline was similarly effective in preventing exacerbations
in pregnant women with moderate asthma but women were
more likely to stop taking it due to side effects [39]. A review of
data from four studies demonstrated no increased risk of total
congenital malformation with first-trimester theophylline
exposure [36]. However, analysis of data for specific malforma-
tions in the Michigan Medicaid study suggested an association
between theophylline use and cardiovascular defects, oral cleft
and spina bifida [32]. Because of the above data, theophylline is
labeled FDA category C for pregnancy.
Long-acting β-agonists
The NAEPP currently recommends the use of long-acting
β2-agonists as an adjunct to ICS therapy in patients with mod-
erate-to-severe persistent asthma because of greater improve-
ment in some outcomes compared with ICS monotherapy and
the desire to use lower doses of ICS [5]. There are no human
data on salmeterol or formoterol during pregnancy, although
there are no reports of congenital defects [7]. These medications
are labeled FDA category C for pregnancy.
Systemic corticosteroids
Oral corticosteroids are administered for acute asthma episodes
in short bursts when a patient fails to respond to short-acting
β2-agonists or chronically in severe, persistent asthma. There are
valid concerns in using systemic steroids, including the question
of increased risk of cleft palates, decreased fetal weight gain and
pre-eclampsia [36,40]. These complications appear to be related to
dosage and duration of treatment, especially in doses over
10 mg/day of prednisone [41]. A recent study by Bakhireva and
69
Streck & Blaiss
colleagues suggests asthma management with β2-agonists
and/or ICS during pregnancy does not impair fetal growth
whereas systemic corticosteroids have a minimal effect which
must be weighed against the necessity to control severe
asthma [42]. Long-term use also carries the risk of hyperglycemia
and can worsen gestational or pre-existing diabetes. Systemic
corticosteroids are labeled FDA category C for pregnancy.
Omalizumab
Omalizumab is an immunoglobulin G monoclonal antibody
directed against immunoglobulin E and is approved for the
treatment of moderate-to-severe allergic asthma that has failed
the use of ICS [43]. Because several women who participated in
studies with omalizumab before FDA approval became
pregnant and delivered normal infants, it has been labeled
category B by the FDA.
New NIH guidelines in management of asthma in pregnancy
In 1993, the Report of the Working Group on Asthma and Preg-
nancy was published by the NAEPP [2]. Since these recommen-
dations for the management of asthma during pregnancy were
presented, there have been revisions to the general asthma treat-
ment guidelines [4,5], as well as the release of new asthma medi-
cations and new data on the gestational safety of medications.
In 2004, the NAEPP published a new set of recommendations
entitled Managing Asthma During Pregnancy: Recommendations
for Pharmacologic Treatment - Update 2004 [20], developed
through a systematic review of the literature to assist the clini-
cian in pharmacologic treatment of the pregnant patient
(TABLES 1–3) (FIGURE 1) [20].
Recommendations for managing asthma during pregnancy:
general principles
The general principles outlined in the aforementioned expert
panel review (EPR) update 2004 are based on the working
group’s interpretation of the current evidence on the safety of
medications during pregnancy and consideration of previous
NAEPP reports. The general principles are as follows:
• The treatment goal for the pregnant asthma patient is to
provide optimal therapy to maintain control of asthma for
maternal health and quality of life as well as for normal
fetal maturation
• It is safer for pregnant women with asthma to be treated with
asthma medications than to have asthma symptoms and
exacerbations. Monitoring and making appropriate adjust-
ments in therapy may be required to maintain lung function
and, hence, blood oxygenation that ensures oxygen supply to
the fetus. Inadequate control of asthma is a greater risk to the
fetus than asthma medications are. Proper control of asthma
should enable a woman with asthma to maintain a normal
pregnancy with little or no risk to her or her fetus
• The obstetrical care provider should be involved in asthma
care, including monitoring of asthma status during prenatal
visits. A team approach is helpful if more than one clinician is
managing a pregnant woman with asthma
70
• Asthma treatment is organized around four components of
management: assessment and monitoring of asthma,
including objective measures of pulmonary function; control
of factors contributing to asthma severity; patient education;
and a stepwise approach to pharmacologic therapy (as
outlined below)
Recommendations for pharmacologic treatment of asthma
during pregnancy
Stepwise approach for managing asthma
To develop recommendations for the stepwise approach to the
pharmacologic treatment of asthma in pregnant women, the
working group first considered the stepwise approach in the
EPR 2002, which was based on systematic review of the evi-
dence from medication effectiveness studies in nonpregnant
adults and children. The effectiveness of medications is
assumed to be the same in pregnant women as in nonpregnant
women, although there are no studies that directly test this
assumption. Based on their current systematic review of evi-
dence from safety studies of asthma medications during preg-
nancy, the working group then tailored existing recommenda-
tions for stepwise therapy. TABLES 1–3 include a complete list of
recommended therapies and medication dosages in the stepwise
approach to managing asthma [20]. The recommendations and
rationale for the preferred medications are described below.
Step 1: mild intermittent asthma
Short-acting bronchodilators, particularly short-acting inhaled
β2-agonists, are recommended as quick-relief medication for
treating symptoms as needed in patients with intermittent
asthma. Salbuterol is the preferred short-acting inhaled β2-ago-
nist because it has an excellent safety profile and the greatest
amount of data related to safety during pregnancy of any cur-
rently available inhaled β2-agoinst. Women’s experience with
these drugs is extensive, and no evidence has been found either
of fetal injury from the use of short-acting inhaled β2-agonists
or of contraindication during lactation.
Step 2: mild persistent asthma
The preferred treatment for long-term control medication is
daily low-dose inhaled corticosteroid. This preference is based
on the strong effectiveness data in nonpregnant women [4,5], as
well as effectiveness and safety data in pregnant women who
show no increased risk of adverse perinatal outcomes. Budeso-
nide is the preferred inhaled corticosteroid because more data
are available on using budesonide in pregnant women than are
available on other inhaled corticosteroids, and the data are reas-
suring. There are no data indicating that the other inhaled cor-
ticosteroid preparations are unsafe during pregnancy. There-
fore, inhaled corticosteroids other than budesonide may be
continued in patients who were well controlled by these agents
prior to pregnancy, especially if it is thought that changing for-
mulations may jeopardize asthma control. Cromolyn, leuko-
triene receptor antagonists and theophylline are listed as alter-
native but not preferred therapies. Cromolyn has an excellent
safety profile, but it has limited effectiveness compared with
Expert Rev. Pharmacoeconomics Outcomes Res. 6(1), (2006)
 Quality of care of asthma during pregnancy

Table 1. Stepwise treatment approach for managing asthma during pregnancy and lactation: treatment.
Classify severity: clinical features before treatment or Medications required to maintain long-term control
adequate control
Step Symptoms PEF or PEF Daily medications
FEV1 variability
Day Night
Step 4: Continual Frequent ≤60% >30 Preferred treatment:
severe High-dose inhaled corticosteroid, long-acting β2-agonist and, if
persistent necessary, corticosteroid tablets or syrup long-term (2 mg/kg/day,
generally not to exceed 60 mg/day). (Make repeat attempts to reduce
systemic corticosteroid and maintain control with high-dose inhaled
corticosteroid*)
Alternative treatment:
High-dose inhaled corticosteroid*, and sustained release theophylline to
serum concentration of 5–12 µg/ml
Step 3: Daily >1 night/week >60 to >30% Preferred treatment:
moderate <80% Either low-dose inhaled corticosteroid* and long-acting inhaled
persistent β2-agonist, or medium-dose inhaled corticosteroid*
If needed, particularly in patients with recurring exacerbations,
medium-dose inhaled corticosteroid* and long-acting inhaled β2-agonist
Alternative treatment:
Low-dose inhaled corticosteroid* and either theophylline or leukotriene
receptor antagonist‡ and, if needed, medium-dose inhaled corticosteroid*
and either theophylline or leukotriene receptor antagonist‡
Step 2: >2 days/ >2 nights/ month >80% 20–30% Preferred treatment:
mild week but Low-dose inhaled corticosteroid*
persistent <daily
Alternative treatment:
Cromolyn, leukotriene receptor antagonist‡ or sustained-release
theophylline to serum concentration of 5–12 µg/ml.
Step 1: ≤2 days/ ≤2 nights/ month ≥80% <20% No daily medication needed
mild week Severe exacerbations may occur, separated by long periods of normal
Intermittent lung function and no symptoms. A course of systemic corticosteroid
is recommended
Quick relief: Short-acting bronchodilator: 2–4 puffs short-acting inhaled β2-agonist as needed for symptoms.
all patients Intensity of treatment will depend on severity of exacerbation: up to three treatments at 20-min intervals or a single nebulizer
treatment as needed. Course of systemic corticosteroid may be needed.
Use of short-acting inhaled β2-agonist‡ >twice a week in intermittent asthma (daily, or increasing use in persistent asthma) may
indicate the need to initiate (increase) long-term control therapy.
Step-up Review treatment every 1–6 months: a gradual stepwise reduction in treatment may be possible
Step-down If control is not maintained, consider step-up. First, review patient medication technique, adherence and environmental control
Goals of Minimal or no chronic symptoms day or night; minimal or no exacerbations; no limitations on activities: no school/work missed;
therapy: maintain (near) normal pulmonary function; minimal use of short-acting inhaled β2-agonist§; minimal or no adverse effects
asthma from medications
control
The stepwise approach is meant to assist, not replace, the clinical decision making required to meet individual patient needs. Classify severity: assign patient to most severe
step in which any feature occurs (peak expiratory flow is percent of personal best; forced expiratory volume in 1 s is percent predicted). Control as quickly as possible
(consider a short course of systemic corticosteroid), then step-down to the least medication necessary to maintain control. Minimize use of short-acting inhaled
β2-agonist§ (e.g., use of approximately one canister per month even if not using it every day indicates inadequate control of asthma and the need to initiate or intensify
long-term control therapy). Provide education on self-management and controlling environmental factors that make asthma worse (e.g., allergens, irritants). Refer to an
asthma specialist if there are difficulties controlling asthma or if Step 4 care is required. May be considered if Step 3 care is required.
*There are more data on using budexonide during pregnancy than on using other inhaled corticosteroids.
‡
There are minimal data on using leukotriene receptor antagonists in humans during pregnancy, although there are reassuring animal data submitted to the FDA.
§
There are more data on using salbuterol during pregnancy than on using other short-acting inhaled β2-agonists.

www.future-drugs.com 71
Streck & Blaiss

inhaled corticosteroids. Leukotriene receptor antagonists have
been demonstrated to provide statistically significant but mod-
est improvements in children and nonpregnant adults with
asthma, although in studies comparing overall efficacy of the
two drugs, most outcomes favor inhaled corticosteroids. Pub-
lished data are minimal on using leukotriene receptor antago-
nists during pregnancy; however, animal safety data submitted
to the FDA are reassuring. Thus, leukotriene receptor antago-
nists are an alternative but not preferred treatment for pregnant
women whose asthma was successfully controlled with this
medication prior to their pregnancy. Theophylline has demon-
strated clinical effectiveness in some studies and has been used
for years in pregnant women with asthma. It also has the poten-
tial for serious toxicity resulting from excessive dosing and/or
select drug–drug interactions. Using theophylline during
pregnancy requires careful titration of the dose and regular
monitoring to maintain the recommended serum theophylline
concentration range of 5–12 µg/ml.
Step 3: moderate persistent asthma
Two preferred treatment options are noted: either a combina-
tion of low-dose inhaled corticosteroid and a long-acting
inhaled β2-agonist, or increasing the dose of inhaled cortico-
steroid to the medium dose range. No data from studies during
pregnancy clearly delineate that one option is recommended
over the other.
Step 4: severe persistent asthma
If additional medication is required after carefully assessing
patient technique and adherence with step 3 medication, then
the inhaled corticosteroid should be increased within the high-
dose range and the use of budesonide is preferred. If this is
insufficient to manage asthma symptoms, then the addition of
systemic corticosteroids is warranted. Although the data are
uncertain about some risks of oral corticosteroids during preg-
nancy, severe uncontrolled asthma poses a definite risk to the
mother and fetus.

Table 2. Usual dosages for long-term control medications during pregnancy and lactation: inhaled corticosteroids.
Adapted from expert panel review update 2002.
Medication Dosage form Adult dose
Systemic corticosteroids (Applies to all three corticosteroids)
Methylprednisolone 2, 4, 8, 16, 32 mg tablets 7.5–60 mg daily in a single dose in morning or every other day as
needed for control
Short-course burst to achieve control: 40–60 mg per day as
single dose or two divided doses for 3–10 days
Prednisolone 5 mg tablets,
5 mg/5 cc,
15 mg/5 cc
Prednisone 1, 2.5, 5, 10, 50 mg tablets,
5 mg/cc, 5 mg/5 cc

Long-acting inhaled β2-agonists (should not be used for symptom relief or for exacerbations, use with inhaled corticosteroids)
Salmeterol MDI 21 µg/puff 2 puffs every 12 h
Formoterol DPI 50 µg/blister 1 blister every 12 h
DPI 12 µg/single-use capsule 1 capsule every 12 h

Combined medication
Fluticasone/salmeterol DPI 100, 250 or 500 µg/50 µg 1 inhalation twice daily: dose depends on severity of asthma

Cromolyn
Cromolyn MDI 1 mg/puff 2–4 puffs 3–4 times daily
Nebulizer 20 mg/ampule 1 ampule 3–4 times daily

Leukotriene receptor antagonists

Montelukast 10 mg tablet 10 mg qhs
Zafirlukast 10 or 20 mg tablet 40 mg daily (20 mg tablet twice daily)

Methylxanthines (serum monitoring is important – serum concentration of 5–12 µcg/ml at steady state)
Theophylline Liquids, sustained release tablets Starting dose 10 mg/kg/day up to 300 mg max: usual max
and capsules 800 mg/day
The most important determinant of appropriate dosing is the clinician’s judgment of the patient’s response to therapy. Some doses may be outside package labeling,
especially in the high-dose range.
DPI: Dry powder inhaler; MDI: Metered dose inhaler.

72 Expert Rev. Pharmacoeconomics Outcomes Res. 6(1), (2006)


Management of acute exacerbations
Asthma exacerbations have the potential to lead to severe prob-
lems for the fetus. Therefore, asthma exacerbations during
pregnancy should be managed aggressively. Home, emergency
department and hospital management plans are outlined in the
EPR update 2004 (see FIGURE 1 for home treatment of asthma
exacerbations) [20].
Quality of care & pregnancy outcomes in patients with asthma
A well-developed management plan is essential for the care of
the pregnant asthmatic patient. The goal of asthma manage-
ment during pregnancy is twofold: to keep the mother symp-
tom free and to prevent complications to the fetus [29]. Tan
and Thomson recommend that all pregnant women with
asthma, except those with the mildest disease, should be
treated by an obstetrician and an asthma specialist [9]. They
emphasize that control of asthma should be optimized precon-
ception and patient education is of paramount importance to
this end. Twice-daily monitoring of peak expiratory flow and
review of peak flow charts may benefit patients with moderate-
to-severe disease. A personalized self-management plan facili-
tates care and will provide guidance for the management of
deteriorating symptoms or flows. Patients are instructed to
seek immediate medical help if an asthma exacerbation is
severe. It is important to reassure pregnant women who have
asthma that their medication carries less risk to the fetus than a
severe asthma attack [44]. Luskin and Lipkowitz state that when
giving any treatment during pregnancy, one must obtain
informed consent. This should include an explanation of the
consequences of failing to prescribe therapy that may alleviate
Table 3. Estimated comparative daily dosages for inhaled corticosteroids. Adapted from expert panel review update 2002.
Drug Adult low daily dose (µg)
Beclomethasone CFC
42 or 84 µg/puff
Beclomethasone HFA
40 or 80 µg/puff
Budesonide DPI
200 µg/inhalation
Flunisolide
250 µg/puff
Fluticasone
MDI: 44, 110 or 220 µg/puff
DPI: 50, 100 or 250 µg/inhalation
Triamcinolone acetonide
100 µg/puff
DPI: Dry powder inhaler; MDI: Metered dose inhaler.
www.future-drugs.com
Quality of care of asthma during pregnancy
the effects of potentially life-threatening asthma to the mother,
fetus or both [45]. Frequent communication between the
patient and the physician is key for optimal management of
asthma during pregnancy [46].
Reluctance to treat may lead to a worsening of asthma during
pregnancy. This is demonstrated in an emergency department
study evaluating short-term treatment for asthma in women that
found that pregnant women were less likely to receive corticoster-
oids (44 vs 66%) than nonpregnant women [47]. The pregnant
patients also had lower peak expiratory flow rates at admission for
status asthmaticus and had longer hospital stays. The pregnant
women were less likely to receive oral corticosteroids at discharge
and had a higher incidence of asthma symptoms at 2-week follow-
up [47]. It is estimated that approximately 18% of all pregnant
asthmatics have at least one emergency department visit, and as
many as 62% of the pregnant women with acute, severe asthma
require hospitalization [31]. Approximately 10% of pregnant asth-
matic patients seek urgent care at some time during their preg-
nancy, especially those not taking ICS [17,30]. Schatz and Leibman
found that for patients using an ICS before pregnancy, the rate of
asthma-related physician visits decreased and the number of ED
visits was unchanged after pregnancy, whereas physician and ED
visits increased after pregnancy for patients not using an ICS
before pregnancy [48]. This suggests that asthma is undertreated in
women contemplating pregnancy and in those who are pregnant.
Bracken and colleagues call attention to the importance of
determining whether pregnancies that are complicated by
asthma or asthma symptoms and actively managed with
currently available pharmacologic therapies are at reduced risk
owing to better management of the underlying disease, or
Adult medium daily dose Adult high daily dose (µg)
(µg)
168–504 504–840 >840
80–240 240–480 >480
200–600 600–1200 >1200
500–1000 1000–2000 >2000
88–264 264–660 >660
100–300 300–750 >750
400–1000 1000–2000 >2000
73
Streck & Blaiss

Assess severity
Measure PEF: value <50% personal best or predicted suggests severe exacerbation
Note signs and symptoms: degree of cough, breathlessness, wheeze and chest
tightness correlate imperfectly with severity of exacerbation
Accessory muscle use and suprasternal retractions suggest severe exacerbation
Note presence of fetal activity

Initial treatment
Short-acting inhaled β2-agonist: up to three treatments of 2–4 puffs by MDI at
20-min intervals or single nebulizer treatment

Good response Incomplete response Poor response

Mild exacerbation: Moderate exacerbation: Severe exacerbation:

PEF >80% predicted or
personal best
No wheezing or shortness of breath
Response to short-acting inhaled
β2-agonist sustained for 4 h
Appropriate fetal activity*
Treatment:
May continue short-acting inhaled
β2-agonist every 3–4 h for 24–48 h
For patients on inhaled
corticosteroid, double dose for
7–10 days
PEF 50–80% predicted or
personal best
Persistent wheezing or shortness
of breath
Decreased fetal activity*
Treatment:
Add oral corticosteroid
Continue short-acting inhaled
β2-agonist
PEF <50% predicted or
personal best
Marked wheezing and shortness
of breath
Decreased fetal activity*
Treatment:
Add oral corticosteroid
Repeat short-acting inhaled
β2-agonist immediately
If distress is severe and non-
responsive, call your clinician
immediately and proceed to
emergency department; consider
calling ambulance or 911

Contact clinician for follow-up Contact clinician urgently Proceed to emergency department
instructions (same day) for instructions

Figure 1. Management of asthma exacerbations during pregnancy and lactation: home treatment.
*Fetal activity is monitored by observing whether fetal kick counts decrease over time.
MDI: Metered dose inhaler; PEF: Peak expiratory flow.

whether risk is increased owing to the therapies themselves [37].
In their study on 2205 pregnancies, they found increased likeli-
hood of preterm delivery with greater medication use, which
appeared to be restricted to theophylline and oral steroids [37].
However, increasing asthma severity and symptoms appeared to
significantly decrease fetal growth, particularly when they
occurred in the absence of an asthma diagnosis.
It is often confusing to dissociate the influence of asthma from
the effect of medications in many studies of treated women.
Asthma has been reported to be associated with increased pre-
term labor and delivery and a low birth weight [49–52]. It is
reported that avoiding acute asthma attacks by using steroids
and theophylline resulted in low birth weight rates equal to the
normal population [51]. Schatz and colleagues reported that
inhaled or oral steroid therapy had no effect on birth weight [19],
and later found that actively managed patients had no increased
risk of intrauterine growth restriction (IUGR), low birth weight
or preterm delivery [27]. A study by Perlow and colleagues con-
sidered asthma severity and showed that severe asthmatics
treated with systemic steroids all had higher rates of preterm
labor, preterm delivery and low-birth-weight infants than non-
steroid-treated severe asthma patients [52], in accordance with
the study by Bracken and colleagues [37]. Martel and colleagues
showed no significant increase of the risk of pregnancy-induced
hypertension or pre-eclampsia among users of ICS during preg-
nancy, while markers of uncontrolled and severe asthma were
found to significantly increase the risks of pregnancy-induced
hypertension and pre-eclampsia [53].

74 Expert Rev. Pharmacoeconomics Outcomes Res. 6(1), (2006)

 Quality of care of asthma during pregnancy

Summary & conclusions
Uncontrolled asthma in pregnant women can lead to peri-
natal complications and exacerbations, which can be devastat-
ing to the mother and the fetus and lead to high medical
costs. Studies have convincingly shown that these risks are
greater than those of adverse effects due to controller medica-
tions, obviating the need for women with asthma to receive
quality care during their pregnancy. The goal of asthma man-
agement during pregnancy is to keep the mother symptom
free and to prevent complications in the fetus. Thus, proper
pharmacotherapy is very cost effective during pregnancy as it
decreases cost now and potential costs in the future. The step-
wise approach to the management of asthma during preg-
nancy is shown to lead to acceptable outcomes that are similar
to the nonasthmatic patient. Although there are no double-
blind, placebo-controlled studies on asthma medications in
pregnant women, large cohort studies have shown the efficacy
of aggressive management. With adequate control of asthma
from the preconception time through delivery, studies have
shown similar outcome in asthmatic patients compared with
nonasthmatics, thus obtaining the goal of a symptom-free
mother and healthy baby.
Expert commentary & five-year view
The quality of care of asthma during pregnancy has signifi-
cantly improved since the implementation of a stepwise strat-
egy for treatment. Though strong recommendations for safe
treatment options have been made by the NAEPP based on a
review of the literature, many patients, as well as physicians, are
still hesitant to treat asthma in pregnancy for fear of causing
harmful outcomes to the fetus. As compliance is already poor
with controller medication in nonpregnant asthmatics, this is
even more likely in the pregnant asthma population. Thus, it is
very important to continue frequent education of our patients
to assure them that appropriately used medication is safer than
poorly controlled asthma during their pregnancy. With aggres-
sive management and follow-up of the pregnant asthmatic
patient, including adherence to the stepwise management strat-
egy, the outcome should be good for both the mother and baby
and lead to decreased overall medical costs.
Due to ethical reasons, it will never be appropriate to per-
form double-blind, placebo-controlled studies in asthmatics
who are or will become pregnant. Thus, we are restricted to
animal studies or observational cohort studies in humans to
determine the safety of medications during pregnancy. Given
that many current asthma medications are relatively new, the
next 5 years hold promise in teaching us their effects on preg-
nancy and the developing fetus. While medications such as
omalizumab and the leukotriene modifiers are considered safe,
we need more time to see if they have any adverse outcomes. As
for ICS, budesonide is currently the recommended medication,
although the 2000 position statement says that it is not unrea-
sonable to use another ICS if the patient was adequately con-
trolled on it prior to pregnancy. Thus, time will likely give us
more data as asthmatic women remain on ICS other than
budesonide during their pregnancies.

Key issues

• Aggressive control of asthma during pregnancy is important for the wellbeing of both the mother and her fetus.
• The incidence of preterm labor, low-birth-weight pregnancies, pre-eclampsia and congenital anomalies are increased in asthmatic
women. If asthma is well controlled, pregnancy outcome may be similar in asthmatic and nonasthmatic women.
• A stepwise approach to the pharmacologic management of asthma based on the expert panel review update 2004 should help
standardize care for pregnant asthmatic patients.
• Reluctance to treat asthmatic patients for fear of adverse outcomes to the fetus is more dangerous than an asthma exacerbation.

References
Papers of special note have been highlighted as:
• of interest
•• of considerable interest
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Affiliations
• Maria R Streck, MD
Fellow in Allergy and Immunology, University of
Tennessee Center for the Health Sciences, College
of Medicine, 50 North Dunlap Street, 4th Floor,
West Patient Tower, Memphis, TN 38103, USA
Tel.: +1 901 572 5377
Fax: +1 901 572 4478
mstreck@utmem.edu
• Michael S Blaiss, MD
Clinical Professor of Pediatrics and Medicine,
University of Tennessee Center for the Health
Sciences, College of Medicine, 7205 Wolf River
Blvd,Germantown, TN 38138, USA
Tel.: +1 901 757 6100
Fax: +1 901 757 0198
mblaiss@allergymemphis.com
77
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