Asthma and Rhinitis During Pregnancy

Immunol Allergy Clin N Am
26 (2006) xi – xii
Foreword
Asthma and Rhinitis During Pregnancy
Rafeul Alam, MD, PhD

Consulting Editor
I am honored to serve as the Consulting Editor for the Immunology and

Allergy Clinics of North America. This series has been at the forefront of
disseminating knowledge from the bench to the bedside. This is not an easy task.
Biological science has enjoyed a hyper-accelerated growth phase thanks to
advances in molecular biology, genomics, and biotechnology. Abnormal gene
functions and molecular defects are identified in human illnesses at an ever-
increasing rate. For this reason, it is very important that clinicians and trainees, as
well as scientists, are kept abreast of the ongoing progress in allergy and
immunology. The interest of our readership is likely to be diverse, and it is not
easy to strike a balance between the basic and clinical science content of the
series. Discoveries in basic science form the foundation for progress in clinical
medicine. Therefore, it is my earnest desire to maintain a fine balance between
basic and clinical science in each issue of this series.
The theme and content of each issue is carefully selected based upon the
perceived need for an update, the depth of recent progress in the field, and the
importance of the theme in the broad field of allergy and clinical immunology.
I receive excellent guidance in this regard from the in-house editors at Elsevier/
Saunders—Sarah Barth and John Vassallo. My utmost gratitude to them for their
help! Once a theme is identified and a guest editor is invited, the bulk of the work
is then done by the guest editor and the invited expert authors. The responsibility
of the guest editor is to conceive the content, identify and invite experts, and
0889-8561/06/$ – see front matter D 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.iac.2005.12.001 immunology.theclinics.com
xii foreword
review and edit the final content. We are grateful to all guest editors for their hard
and time-consuming work.
Management of diseases during pregnancy is always a challenge. Our knowl-
edge about the physiology of pregnancy is incomplete. Maintaining a balance
between maternal health benefits from drugs and their potential toxicity for
the growing fetus is extremely important. We have brought together a group of
experts led by Michael Schatz, who is a well-recognized authority in the field.
They have prepared an outstanding update on the latest developments in asthma
and rhinitis during pregnancy. The issue addresses respiratory physiology, clinical
course and management of asthma, allergic conditions during pregnancy and
lactation, and, finally, safety of medications in pregnancy. The issue is timely and
important. I hope you enjoy it.
Rafeul Alam, MD, PhD

Division of Allergy & Immunology
National Jewish Medical and Research Center
1400 Jackson Street
Denver, CO 80206, USA
E-mail address: alamr@njc.org
26 (2006) xiii – xiv
Preface
Asthma and Rhinitis During Pregnancy
Michael Schatz, MD, MS

Guest Editor
Asthma complicates up to 8% of pregnancies, and nasal symptoms occur in

at least 30% of pregnant women. Certain types of respiratory infections may
occur more commonly in patients who have asthma, rhinitis, or are pregnant.
When patients and their caregivers are faced with these common problems during
pregnancy, several important questions almost always arise. Usually foremost on
the woman’s mind are the potential effects of the treatment on the developing
baby. The physician and, frequently, the patient are also concerned about the
effects of pregnancy on the medical condition, as well as the potential effects
of the asthma or rhinitis on the mother, her pregnancy, and the infant. Finally, the
ultimate question that must be answered is: What is the best way to manage
the asthma, rhinitis, or respiratory infection during pregnancy so as to optimize
the health of both the mother and the baby? To provide the best current answers
to these questions and the information on which those answers are based, this
issue of the Immunology and Allergy Clinics of North America brings together
authors from several disciplines, including allergy–immunology, pediatrics,
emergency medicine, epidemiology, maternal–fetal medicine, otorhinolaryngol-
ogy, and pulmonary medicine.
The first article sets the stage for understanding respiratory problems during
pregnancy by reviewing the pulmonary physiologic changes associated with preg-
nancy. The next article provides the basis for recommendations regarding the use
xiv preface
of asthma and rhinitis medications during pregnancy, a topic of prime interest to

patients and their providers.
The next several articles deal with various aspects of asthma. The article on
asthma epidemiology during pregnancy provides a population context for
understanding the prevalence and impact of gestational asthma, including symp-
toms, acute episodes, treatment, and their relationships to demographic factors.
Pregnancy often affects the course of asthma, and the next article discusses what
is known clinically and mechanistically about these effects. The important con-
cern regarding the effect of asthma on the outcome of pregnancy is covered in the
next article, again from both a clinical and a mechanistic perspective. Finally, the
next two articles describe the recommended management of chronic and acute
asthma during pregnancy.
Rhinitis and respiratory infections are even more common than asthma during
pregnancy. The article on rhinitis of pregnancy describes what the literature tells
us regarding this interesting gestational problem in terms of its clinical mani-
festations, possible etiology, and treatment. A frequent problem in women of
child-bearing age is allergic rhinitis, and the next article describes the differential
diagnosis, course, and management of this common problem during pregnancy.
Finally, the diagnosis and management during pregnancy of important respiratory
infections, including sinusitis and pneumonia, are covered in the last article.
Pregnancy is a very special period in a woman’s life. However, when this time
is complicated by asthma, rhinitis, or respiratory infection, it may be much more
difficult for both the woman and her physicians. I very much hope that the in-
formation provided in this issue will be useful to physicians caring for pregnant
women who have asthma, rhinitis, or respiratory infections and ultimately help
to optimize the health of these pregnant women and their infants.
Michael Schatz, MD, MS

Department of Allergy
Kaiser Permanente Medical Center
7060 Clairemont Mesa Boulevard
San Diego, CA 92111, USA
E-mail address: michael.x.schatz@kp.org
26 (2006) 1 – 12
Respiratory Physiologic Changes in Pregnancy

Robert A. Wise, MDT, Albert J. Polito, MD,
Vidya Krishnan, MD, MHS
Department of Medicine (Pulmonary and Critical Care Medicine),
Johns Hopkins University School of Medicine, 5501 Hopkins Bayview Circle,
Baltimore, MD 21224, USA
This article reviews the respiratory functional changes that accompany preg-
nancy. Pregnancy is associated with enormous hormonal, circulatory, and mechani-
cal alterations. The pregnant state is accompanied by increases in progesterone
and estrogen with vascular and central nervous system effects, alterations in the
balance of bronchoconstrictor and bronchodilator prostanoids, and increased
levels of peptide hormones that alter connective tissue characteristics. Cardiac out-
put and pulmonary blood flow are increased because of the metabolic demands
of the products of conception, the increase in blood volume, and the decrease in
hemoglobin concentration. The plasma oncotic pressure is decreased because of
the increase in blood volume and decrease in albumin concentration. The com-
bination of increased pulmonary blood flow, increased pulmonary capillary blood
volume, and decreased oncotic pressure all promote the formation of edema in the
periphery and in the lung. The course of pregnancy is accompanied by structural
changes to the ribcage and abdominal compartments as a consequence of the
hormonal changes and the enlarged uterus. Given the dramatic physical and hor-
monal alterations of pregnancy, perhaps the most remarkable aspect of respiratory
physiology is the minor impact that pregnancy has on the function of the lung.
Over the years, there have been several excellent reviews of the effects of preg-
nancy on the respiratory system in health and disease. [1–5]. This article is an
update of a previous paper that appeared in this journal in 2000 [6].
Portions of this article were previously published in Wise RA, Polito AJ. Respiratory physiologic
changes in pregnancy. Immunol Allergy Clin North Am 2000;20(4):663–72.
T Corresponding author.
E-mail address: rwise@jhmi.edu (R.A. Wise).
2 wise et al
Effect of pregnancy on ventilation and gas exchange
Resting minute ventilation increases during pregnancy [7–9]. This is primarily

due to an increase in tidal volume with a constant breathing rate and pattern.
Because the dead space/tidal volume ratio remains normal during pregnancy, the
increased tidal volume leads to increased alveolar ventilation [10]. Most studies
find that this hyperventilation occurs early in pregnancy during the first trimester,
and stays constant or increases slightly as pregnancy progresses [11]. Typically,
resting minute ventilation is increased about 30% during pregnancy compared
with the postpartum value. In part, the increase in minute ventilation is caused by
an increase in metabolic rate and carbon dioxide (CO2) production. During
pregnancy, CO2 production at rest increases by about 30% to 300 mL/minute.
The increase in minute ventilation exceeds that which is required to maintain
a normal arterial carbon dioxide level. As a result, the Paco2 decreases from
40 mm Hg in the nonpregnant state to 32 to 34 mm Hg in pregnancy [12]. The
kidney excretes excess bicarbonate to compensate for the respiratory alkalosis,
and maintains a serum bicarbonate level of about 15 to 20 mEq/L to preserve
a normal arterial pH. The respiratory alkalosis causes a rightward shift in the
oxyhemoglobin dissociation curve that favors the unloading of oxygen in the
periphery, and presumably aids oxygen transfer across the placenta [13].
There is general agreement that the main cause of the increased respiratory
drive that causes the hyperpnea of pregnancy is the elevation of serum pro-
gesterone, a direct respiratory stimulant. The progesterone-induced increase in
chemosensitivity results in an increase in the slope and a leftward shift of the
CO2 ventilatory response curve. The increase in chemosensitivity occurs early in
pregnancy and remains constant up until delivery. The respiratory center output,
which integrates chemical and mechanical stimuli, is measured by the mouth
pressure 100 milliseconds after airway occlusion. This measure increases
progressively throughout pregnancy, and is compatible with the idea that the
hyperpnea of pregnancy is the result of increased chemosensitivity and the load
imposed by the gravid uterus. Shortly after delivery, the respiratory drive returns
to normal with the decrease in progesterone levels and the reduction in metabolic
and mechanical loads that were induced by pregnancy.
The evidence that progesterone is a respiratory stimulant is strong [14]. When
progesterone is administered to nonpregnant individuals, it increases minute
ventilation, CO2 chemosensitivity, and airway occlusion pressure [15–17]. It has
been debated whether progesterone acts through a direct stimulatory effect on
the respiratory center or through an increase in the gain of the chemoreceptors
[18]. The most recent evidence shows that the threshold for hypercapnic venti-
lation and the gain in ventilation is increased in pregnancy, which suggests that
intrinsic and chemically driven responses are more sensitive in the pregnant
hormonal milieu [19].
The hypoxic ventilatory response is increased in pregnancy to about twice
the normal level [20]. This occurs despite the blood and cerebrospinal fluid
alkalosis that tends to suppress hypoxic drive. In contrast to the response to
respiratory physiologic changes in pregnancy 3
CO2, the hypoxic ventilatory response in pregnancy does not correlate well with
progesterone levels. It is believed that the increased sensitivity to hypoxia is due
to the increases in estrogen and progesterone [21,22].
Arterial oxygen tensions are increased slightly in pregnancy as a result of the
pregnancy-induced hyperpnea, with a normal pregnant level of 100 to 105 mm Hg
[10]. This higher level of oxygen tension may facilitate oxygen transfer across
the placenta by diffusion; however, the increased metabolic rate and the low
oxygen reservoir in the lung at end expiration make the pregnant woman par-
ticularly susceptible to develop hypoxemia in the presence of respiratory depres-
sion or apnea [23,24]. In some women, the low end-expiratory lung volume may
predispose them to decreasing oxygen tensions in the supine position [25].
The overall effect of pregnancy on the diffusing capacity for carbon mon-
oxide (Dco) is determined by the relative contributions of opposing physiologic
changes. Pulmonary blood volume and cardiac output are increased in pregnancy,
which should recruit capillary surface area, and thereby, increase Dco. This is
offset by the dilutional reduction in hemoglobin concentration that occurs, and
leads to a constant or slightly diminished Dco in most pregnant patients [26].
The normal increase in Dco that occurs in the supine position is absent in
pregnancy, which might indicate that the gravid uterus prevents the normal
increase in systemic venous return, or that the pulmonary capillary bed is already
fully recruited [27]. The latter explanation is less plausible because exercise
causes a normal increase in Dco in pregnant women [28]. One study suggests that
there are different effects of pregnancy on Dco in high-altitude dwellers. Pregnant
women who dwell at high altitude have a higher Dco than those who live at sea
level; however, during the third trimester they have a lower Dco than non-
pregnant women who live at high altitude. At sea level, the Dco is similar
throughout pregnancy compared with nonpregnant controls [29].
Physiologic dyspnea of pregnancy
The increase in minute ventilation that accompanies pregnancy often is per-

ceived as shortness of breath. Approximately 75% of pregnant women have
exertional dyspnea by 30 weeks of gestation [30–33]. Shortness of breath at rest
or with mild exertion is so common that it often is referred to as ‘‘physiologic
dyspnea.’’ The proposed causes of dyspnea are the increased drive to breath
and the increased respiratory load. The increase in minute ventilation and the
load that is imposed by the enlarging uterus cause an increase in the work of
breathing. Other factors that are believed to contribute to the sensation of dys-
pnea include increased pulmonary blood volume, anemia, and nasal congestion.
Studies of the psycho-physiology of dyspnea in pregnancy indicate that the
dyspnea can be accounted for by the increased effort of breathing, rather than
an increased sensitivity to mechanical loads [34].
The cardiovascular response to endurance exercise in late pregnancy is un-
changed compared with the postpartum state [35]. Similarly, exercise efficiency
4 wise et al
(change in oxygen consumption per change in work load) is unchanged [36];

however, ventilation at any level of oxygen consumption or CO2 production is
increased in pregnancy, which leads to increased perception of respiratory effort.
This excess exercise ventilation and sensation of breathlessness can be reduced
by aerobic training [37].
It can be challenging for a physician to differentiate the normal dyspnea
of pregnancy from that which is due to disease pathology. Findings that raise
the question of pathologic dyspnea include increased respiratory rate greater
than 20 breaths per minute, Paco2 that is less than 30 mm Hg or greater than
35 mm Hg, or abnormal measures on forced expiratory spirometry or cardiac
echocardiography. The time course of symptoms also is helpful in differentiating
pathologic conditions. Abrupt or paroxysmal episodes of dyspnea suggest an ab-
normal condition.
Lung and chest wall mechanics in pregnancy
Lung volumes have been measured in several case series of pregnant women,
in comparison with nonpregnant women or with the postpartum state. At term,
helium dilution lung volumes may underestimate the true lung volume by 0.2 to
0.5 L because the low end-expiratory lung volume may impinge upon the closing
volume, and thereby, prevent equilibration with the helium. If accurate measures
of lung volume are required in term pregnancy, then body plethysmography is the
preferred technique [38]. The consensus of many studies is that lung volumes
mostly are well preserved in pregnancy. The total lung capacity usually is pre-
served or is decreased minimally. The residual volume tends to decrease slightly,
which leads to a small increase or stability of the vital capacity [39–46]. The most
consistent change in static lung volumes with pregnancy is the reduction in
functional residual capacity (FRC) and the expiratory reserve volume. As the
uterus enlarges, FRC decreases by 10% to 25% of the previous value, starting
about the twelfth week of pregnancy [39]. The normal reduction in FRC in the
supine position is accentuated further in pregnancy [47,48]. The reduction in
FRC is due to a decrease in chest wall compliance, which decreases about 35%
to 40% [49]. The lung compliance remains normal during pregnancy, whereas
expiratory muscle strength is in the low-normal range [40].
The decreased chest wall compliance is the result of the enlarging uterus in-
creasing the abdominal pressure, because the reduction in FRC is correlated with
the increase in end-expiratory abdominal pressure, but not end-expiratory pleural
pressure [50]. The diaphragm elevates about 4 cm and the circumference of the
lower rib cage increases about 5 cm [41]. The lower end-expiratory lung volume
leads to an increased area of apposition of the diaphragm to the chest wall, which
improves the coupling of the diaphragm and chest wall [51]. Thus, the increased
tidal volume of pregnancy is achieved without an increase in the respiratory
excursions of the diaphragm.
The rib cage undergoes structural changes during pregnancy from the changes
in the hormonal milieu [52]. Progressive relaxation of the ligamentous attach-
ments of the ribs causes the subcostal angle of the rib cage to increase from 688 to
1038 early in pregnancy, before the uterus is enlarged substantially. This change
persists for months after the end of pregnancy when the uterus returns to nor-
mal size. The increased elasticity of the rib cage probably is the result of the
same factors that induce changes in the elastic properties of the pelvis. One of
the important mediators is believed to be the polypeptide hormone, relaxin, which
is increased during pregnancy. This substance is responsible for the softening of
the cervix and the relaxation of the pelvic ligaments [53,54].
Airflow mechanics
Forced expiratory spirometry is useful to follow patients who have asthma.

Therefore, it is important that clinicians understand that pregnancy has no
significant effect on the forced expiratory volume in 1 second (FEV1) or the
FEV1/forced vital capacity (FVC) ratio [26,55,56]. Peak expiratory flow rates
have been reported to remain close to the normal range and be unchanged during
pregnancy [57]. A more recent study described a small, but statistically sig-
nificant, decrease in peak expiratory flow rates with advancing pregnancy,
especially in the supine position [58]. The shape of the flow-volume curve and
absolute flow rates at low lung volumes are normal in pregnant women [27].
Thus, it is possible to use nonpregnant reference values to evaluate lung function
in pregnant women. A reduction in FEV1 or FVC should not be attributed to
pregnancy alone. Measurement of airway conductance by several methods
demonstrates normal or increased large airway conductance [40,55]. A recent
epidemiologic study raised the possibility that pregnancy may induce changes in
the lung that improve airway function and persist throughout life [59]. Small
airway function, as measured by closing volume, is normal [60–62]; however,
because the FRC is low, airways may close during tidal breathing and increase
the alveolar–arterial oxygen gradient in the supine position.
Sleep and pregnancy
Sleep disturbances are common during pregnancy as the result of bio-

chemical and physical changes. The American Academy of Sleep Medicine
defines a clinical entity of ‘‘pregnancy-associated sleep disorder’’ as the occur-
rence of insomnia or excessive sleepiness that develops in the course of preg-
nancy [63].
Estrogen causes alterations in the upper airway, including mucosal edema,
hyperemia, and mucus hypersecretion, which can increase upper airway resis-
6 wise et al
tance. Progesterone has a strong sedating effect, which may be a teleologic pro-
tection during pregnancy to rest. Cortisol level is increased during pregnancy, and
is associated with clinical depression and its associated sleep changes (increased
rapid eye movement [REM] density and decreased REM latency). Physical
changes in pregnancy, including abdominal distension, fetal movement, bladder
distention, urinary frequency, backache, and heartburn, all contribute to the re-
duced sleep efficiency and increased nocturnal awakenings.
Pregnant women have increased complaints of insomnia and daytime sleepi-
ness. Sleep quality reportedly is worsened in the first and third trimesters, with
frequent nocturnal awakenings. Polysomnography reveals reduced slow wave
and REM phases of sleep, and increased total sleep time and wake after sleep
onset, all of which progress during the course of the pregnancy. Sleep efficiency
also is reduced, and remains poor up to 3 months post partum [64,65]. Snoring is
common during pregnancy; it occurs in 14% to 23% of pregnant women by the
third trimester, as compared with 4% of nonpregnant, age-matched controls [66].
Of concern is that snoring during pregnancy may be associated with pregnancy-
induced hypertension and intrauterine growth retardation [67].
Sleep disorders may occur more frequently in the gravid female patient. Sleep
disordered breathing, a spectrum of respiratory disorders during sleep, including
obstructive and central sleep apnea, periodic breathing, and nocturnal hypo-
ventilation, is uncommon in otherwise healthy young women, but changes in
pregnancy alter the risk of developing sleep disordered breathing. Weight gain
and increased upper airway resistance that are due to estrogen effects may pre-
cipitate or worsen preexisting sleep apnea; increased minute ventilation, prefer-
ence for the lateral sleep posture, and decreased REM sleep time can decrease the
risk of sleep apnea [64]. Restless leg syndrome (RLS), a sensory disorder in
which patients describe an uncontrollable urge to move the legs while in the
recumbent position at night, can disrupt sleep significantly. In one large study
from Japan, prevalence of RLS in pregnant women (who did not have RLS
before pregnancy) ranged from 15% in the first trimester to 23% by the final
trimester [68]. This increased prevalence may reflect relative iron or folate
deficiency during pregnancy [69,70].
Effect of pregnancy on chronic pulmonary diseases
Clinicians who care for pregnant women who have underlying pulmonary
disorders should understand that deviations from normal values of arterial oxy-
genation, FEV1, FVC, diffusing capacity, and respiratory rate indicate patho-
logic conditions. In contrast, a normal nongravid value of 40 mm Hg for the
Paco2 in a pregnant patient should be considered evidence of respiratory fail-
ure and be treated accordingly. The effect of pregnancy on asthma and allergic
diseases is treated extensively elsewhere in this issue. Other chronic respiratory
diseases also may be affected—beneficially and adversely—by pregnancy.
Sarcoidosis is the classic example of a disease that tends to stabilize or im-

prove during pregnancy [71–76]. It is the most common of the interstitial lung
diseases to complicate pregnancy. The observed increase in circulating free cor-
tisol in pregnant women has been postulated as the explanation for the im-
provement that is seen in some patients [77]. This also may explain why
patients who have autoimmune disorders, including rheumatoid arthritis and
systemic lupus erythematosus with their attendant pulmonary involvement,
frequently stabilize during pregnancy [77–79]. Cytotoxic agents that might be
used for autoimmune disorders are contraindicated in pregnancy because of their
teratologic and abortifacient effects. Corticosteroids have been used in pregnancy,
although they may lead to preterm delivery or intrauterine growth retardation
[79]. As with asthma, however, the effect of the use of higher doses of cortico-
steroids cannot be separated clearly from the impact of increased disease activity
that prompts the use of these agents.
In contrast to the immune-mediated interstitial lung diseases, lymphangio-
leiomyomatosis (LAM), an uncommon interstitial lung disease that occurs ex-
clusively in fertile women, typically is worsened by pregnancy [80–84]. This is
not surprising given the hypothesis that disease progression in LAM is estrogen-
mediated. Consequently, most women who have LAM are advised to avoid
pregnancy [85].
The mean age of survival of patients who have cystic fibrosis has increased
progressively over the last several decades. With this change, an increasing num-
ber of women who have cystic fibrosis are choosing to become pregnant. With
careful management, such patients are generally able to tolerate pregnancy well
[86–88]. An FVC of more than 50% of predicted has been offered as a safe
threshold for pregnancy; however, other factors, including frequency of pulmo-
nary exacerbations, nutritional status, and presence of pulmonary hypertension,
must be taken into account [89,90].
The physiologic changes in the cardiovascular and respiratory systems during
pregnancy are tolerated poorly by certain groups of patients. A large body of
literature has described the problems that are induced by the increased cardiac
output demands of pregnancy in patients who have primary and secondary pul-
monary hypertension [91–94]. Chronic obstructive pulmonary disease [95,96]
and neuromuscular disease [97] also generally predispose to poor outcomes
because they add to the increased work of breathing that is imposed by preg-
nancy. Among the neuromuscular disorders, myasthenia gravis presents a special
case. Two thirds of myasthenic women remain the same or show improvement in
their disease during pregnancy, whereas one third worsen [76].
Although pregnancy generally is not considered to be an immunocompro-
mised state, several chronic infections, most notably tuberculosis [98,99] and coc-
cidioidomycosis [100,101], may reactivate or worsen in the gravid setting. This
may be due, in part, to changes in the number and function of T and B lympho-
cytes [102–104], but hormonal alterations also may play a role. For example, es-
trogen was demonstrated to enhance the growth of Coccidioides immitis in vitro
[105]. Antituberculous and antifungal chemotherapy are useful in these settings.
8 wise et al
Pulmonary embolic disease in pregnancy
The two leading causes of unexpected maternal deaths are thromboembolic

disease and amniotic fluid embolism [106]. Pregnancy increases the risk of ve-
nous thromboembolism formation by the hypercoagulable effects of estrogen
and venous stasis that are due to increased intra-abdominal pressure [107]. Am-
niotic fluid embolism may result in acute lung injury by causing pulmonary vas-
cular endothelial damage, complement activation, and direct platelet aggregation
effects of amniotic fluid [108–110]. Air embolism is an uncommon complication
of pregnancy in which air enters the venous circulation through the subplacental
myometrial veins, and results in endothelial damage and mechanical obstruction.
Summary
In summary, the major physiologic changes that occur in pregnancy are the
increased minute ventilation, which is caused by increased respiratory center
sensitivity and drive; a compensated respiratory alkalosis; and a low expiratory
reserve volume. The vital capacity and measures of forced expiration are well
preserved. Patients who have many lung diseases tolerate pregnancy well, with
the exception of those who have pulmonary hypertension or chronic respiratory
insufficiency from parenchymal or neuromuscular disease.
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26 (2006) 13 – 28
Safety of Asthma and Allergy Medications

in Pregnancy
Christina Chambers, PhD, MPH
Department of Pediatrics and Family and Preventative Medicine,
University of California San Diego Medical Center, 200 West Arbor Drive, #8446, San Diego,
CA 92103-8446, USA
Up until the second half of the 20th century, the fetus was believed to occupy
a privileged spot, where it was protected from insults that originated from the
external environment. Birth defects were assumed to have a genetic etiology.
That changed in l961 when Lenz [1] in West Germany and McBride [2] in
Australia independently reported that thalidomide, a fairly commonly prescribed
sedative, caused serious problems for the developing embryo when taken be-
tween the 20th and 36th day after conception,. Over the ensuing 50 years, the
pendulum swung precipitously in the opposite direction to a situation today in
which women and their health care providers must consider safety issues for any
medications that are used during pregnancy. Surprisingly, for most drugs that are
taken by women during their pregnancy, inadequate human data are available to
support those decisions.
Typically, the safety of new medications cannot be evaluated ethically in
pregnant women during premarketing clinical trials. Thus, when a new medi-
cation is approved for use, premarketing animal reproductive toxicity studies
generally are the only source of safety information regarding pregnancy. Owing
to species specificity and sensitivity to reproductive toxins, it is difficult to ex-
trapolate with confidence from animal studies to human pregnancy. Nevertheless,
this usually is the only information that the clinician has available to rely on for
evaluating the safety of most medications. Despite its limited relevance, these
data often are the only information that is available to consider in assigning the
pregnancy label category for drug safety [3].
In the postmarketing arena, information on drug safety in pregnancy can be
obtained through case reports that appear in the literature; adverse event reporting
E-mail address: cchambers@ucsd.edu
14 chambers
systems, such as the program managed by the U.S. Food and Drug Admin-
istration; pregnancy registries; birth defects surveillance programs; observational
cohort studies; case-control studies; and large database linkage studies. Each of
these approaches has strengths and limitations. Even for medications that are used
commonly by pregnant women, the sample sizes that are required to rule out risks
for rare events (eg, specific major birth defects) are difficult to achieve, even
when resources are devoted to these efforts. Moreover, no single type of study or
source of data usually is sufficient to address adequately the risks for the spec-
trum of pregnancy outcomes that might be associated with a given medication
used in pregnancy [4].
Therefore, clinical decision-making regarding drug safety in pregnancy is a
challenge at best. Medications that are used for the treatment of asthma and
rhinitis are not exceptions. Because asthma is one of the most common, poten-
tially serious chronic diseases in women of reproductive age—occurring in 3.7%
to 8.4% of all pregnancies [5]—and allergy occurs in greater than 20% of women
of child-bearing age [6], the clinician frequently is required to interpret available
data in the context of almost universal lack of comprehensive safety information
on the medications that are used to treat these conditions.
This article summarizes available human data regarding pregnancy outcome
in women who take various medications for the treatment of asthma and rhini-
tis during pregnancy. Where possible, the potential contribution of the maternal
underlying disease is taken into consideration, and the strengths and limitations
of existing data are emphasized, including methodologic issues in published
studies. Finally, a list of resources for further information that is continually
updated is provided.
Medications used for the treatment of asthma in pregnancy
Published studies of pregnancy outcome in asthmatic women who were

treated with a variety of medications have produced inconsistent results, with
increased risks for birth defects overall, and specifically, oral clefts, spontaneous
abortion or stillbirth, preterm delivery or shortened gestational age, preeclampsia,
low or reduced birth weight, neonatal hypoxia, cesarean section, and hemorrhage
noted in some studies [7].
In the following text and accompanying tables, summaries of the available
human data are provided for each medication category with respect to increased
risks for major birth defects overall, specific birth defects, birth size, preterm
delivery, and preeclampsia.
Although spontaneous abortion also is an adverse outcome of interest that
could occur more frequently in asthmatic women, well-designed studies to exam-
ine rates of spontaneous abortion are infrequent. The greatest risk for this event
typically occurs before clinical recognition of pregnancy, which makes it difficult
to identify most women who have experienced a pregnancy loss. Nevertheless,
one cohort study that was conducted by Schatz and colleagues [8] compared rates
asthma & allergy medications in pregnancy 15
of spontaneous abortion among 824 asthmatic women and 678 nonasthmatic

women who were receiving care through a large health maintenance organiza-
tion in San Diego, California. Although rates of spontaneous abortion were
increased significantly among asthmatics relative to controls, there was no
evidence that any specific asthma medication carried more risk than another. This
suggested that if a risk exists, it may be related to the disease, rather than the
treatment. Furthermore, because asthmatic women tended to enter the study
earlier, the excess risk for spontaneous abortion may have been related to the
timing of enrollment.
Theophylline
Selected studies of pregnancy outcomes associated with theophylline use are

shown in Table 1. Using a retrospective cohort design in which 212 pregnant
asthmatic women who were treated with theophylline were compared with
292 pregnant asthmatics without exposure to theophylline and 237 nonasthmatic
Table 1
Summary of selected studies on theophylline
P value
Investigators Source of or Odds
or study [reg] Design subjects No. of subjects End points ratio (OR)
Stenius Retrospective Clinic/hospital- 212 exposed Congenital NS
Aarniala cohort based Finland asthmatics anomalies
et al [9] 292 unexposed Low birth NS
asthmatics weight
237 nonasthmatic Perinatal death NS
controls Preterm delivery NS
Preeclampsia NSa
Schatz et al Cohort U.S. multicenter 2123 asthmatics Congenital NS
[10] MFMU Network 273 exposed anomalies
Low birth weight NS
Perinatal death NS
Preterm delivery NS
Preeclampsia/PIH NS
Collaborative Cohort U.S. multicenter 55,000 women Congenital NS
Perinatal 117 exposed anomalies
Project [12]
Michigan Database U.S. medical 1240 ‘‘exposed’’ Congenital NS
Medicaid claims Data anomalies
[11]
Bracken et al Cohort Practice/clinic- 2379 enrolled Low birth NS
[13] based U.S. 872 asthmatic weight
northeast 1333 controls Preterm Adjusted
15 exposed delivery OR 1.1
(CI, 1.0, 1.1)
Abbreviations: CI, confidence interval; MFMU, U.S. National Institute of Child Health and Develop-
ment Maternal Fetal Medicine Units; NS, not significant; PIH, pregnancy-induced hypertension.
a
Not significant compared with other asthmatics but increased relative to nonasthmatics.
16 chambers
pregnant control women, Stenius-Aarniala and colleagues [9] found no signifi-

cantly increased risks for major congenital anomalies, reduced birth weight,
perinatal death, or preterm delivery. An increased risk for preeclampsia was noted
in theophylline-exposed women compared with nonasthmatic women (15.6%
versus 6.4%, P b.03), but not compared with other asthmatic women. This sug-
gested that theophylline-treated asthmatic patients may have had more severe
underlying disease. Consistent with that conclusion, Stenius-Aarniala and col-
leagues noted that 19% of the women in their theophylline-treated group reported
acute exacerbations of asthma as compared with 6% in the group of asthmatic
women without exposure to theophylline ( P b.001).
Using data from 16 centers involved in the U.S. National Institute of Child
Health and Development Maternal Fetal Medicine Units Network (MFMU),
Schatz and colleagues [10] reported on pregnancy outcome among 2123 asth-
matic women who were enrolled between 1994 and 2000. These investigators
found no increased risks for congenital anomalies, low birth weight, preterm de-
livery, or preeclampsia among 273 theophylline-exposed women compared with
asthmatics who did not use the drug.
Similarly, in medical claims data from Michigan that were analyzed by Rosa
[11], the rates of major congenital anomalies among 1240 pregnant women
who received a prescription for theophylline were not substantially higher than
expected rates in the general population [11]. The Michigan Medicaid data are
not based on validated exposure information, there is no control group, and the
data have not been peer-reviewed. Finally, in 117 first trimester theophylline-
exposed pregnancies that were identified through the Collaborative Perinatal
Project—a large prospective multisite cohort study that was conducted in the
1960s—no significant increased risk for all major congenital anomalies combined
was seen, compared with unexposed women [12]. Although no significantly
increased risk for major birth defects was noted with first trimester exposure to
theophylline in any of the studies cited above, sample sizes in each study were
insufficient to rule out anything but high relative risks for major birth defects
overall or for any specific birth defect.
In one additional study that addressed only low birth weight and preterm
delivery as outcomes, Bracken and colleagues [13] prospectively recruited
872 asthmatic and 1333 nonasthmatic women from clinics in Connecticut and
Massachusetts. Although an increased risk for low birth weight was not seen
among women who used theophylline, the odds of preterm delivery were ele-
vated significantly compared with unexposed women. In multivariate analysis,
there was an estimated 5% increase in risk for each additional dose per month
(adjusted odds ratio [OR], 1.05; 95% confidence interval [CI], l.01–1.09) in the
15 women who used theophylline at anytime in pregnancy.
Short-acting b2 agonists
Selected studies that addressed the effects of short-acting bronchodilators on

pregnancy outcome are shown in Table 2. Data on major congenital anomalies
Table 2
Summary of selected studies on short-acting b2 agonist medications
Investigators or
study [ref] Design Source of subjects No. of subjects End points P value
Collaborative Cohort U.S. multicenter 55,000 women Congenital NS
Perinatal 373 ephedrine anomalies
Project [12] 189 epinephrine
Michigan Database U.S. medical 1090 albuterol Congenital NS
Medicaid [11] claims data 361 metaproterenol anomalies
149 terbutaline
Schatz et al [8] Cohort U.S. hospital/clinic- 1000 unexposed Congenital NS
based southwest 488 exposed anomalies
Low birth NS
weight
Preterm NS
delivery
Preeclampsia/ NS
PIH
Schatz Cohort U.S. multicenter 295 unexposed Congenital NS
et al [10] MFMU Network 1753 exposed anomalies
Low birth NS
weight
Preterm NS
delivery
Preeclampsia/ NS
PIH
Bracken Cohort Practice/clinic- 1800 unexposed Low birth NS
et al [13] based U.S. northeast 401 exposed weight
1676 unexposed Preterm NS
529 exposed delivery
Abbreviations: NS, not significant; PIH, pregnancy-induced hypertension.
from the Collaborative Perinatal Project showed no significant increased risk

for defects overall in 373 women who were exposed to ephedrine in the first
trimester; however, among 189 women who were exposed to epinephrine, a sig-
nificantly elevated relative risk of 1.7, for all major birth defects combined
(P b.05), was reported [12].
In the Michigan Medicaid claims dataset, 1090 women who received pre-
scriptions for albuterol, 361 who were prescribed metaproterenol, and 149 who
received terbutaline did not demonstrate any excess of major malformations over
the number expected [11]. Similarly, in the 1997 Kaiser Study authored by Schatz
and colleagues [8] as well as the 2004 MFMU study [10] described above, no
increased risk for major birth defects was shown among 488 and 1753 b2 agonists
users, respectively, compared with nonasthmatic women in the earlier study and
with unexposed asthmatic patients in the latter study. Metaproteranol, terbutaline,
and albuterol were the most common agents in the 1997 study, whereas albuterol
was the only short-acting bronchodilator reported in the MFMU study. Again,
although there is reassuring consistency of the data regarding safety, numbers in
18 chambers
these cohort studies do not allow for any conclusions to be drawn about increased
risks for specific major birth defects.
With respect to other perinatal outcomes, neither the 1997 Kaiser study [8] nor
the MFMU study [10] showed any indication of increased risks for preterm
delivery, low birth weight, gestational hypertension, or preeclampsia. These find-
ings were corroborated by Bracken and colleagues [13], who noted no signifi-
cant increased risk for preterm delivery (OR, 1.14; 95% CI, 0.79–1.66) among
529 women who were exposed to short-acting b2 agonists, and no increased
risk for low birth weight among 401 women with exposure in the third trimester
(OR ,0.97; 95%, CI 0.65–1.47).
Long-acting b2 agonists
Only a few studies have examined pregnancy outcomes with prenatal ex-
posure to long-acting b2 agonists (Table 3). These include two studies by Wilton
and colleagues [14,15], drawn from a prescription event monitoring program in
Great Britain, which is designed to collect case reports of pregnancy outcomes
for newly marketed medications. This system received reports of 91 pregnancy
exposures to salmeterol, among which 65 infants who had first-trimester ex-
posure were live born. Rates of congenital anomalies (2%), spontaneous abor-
tion (8%), and preterm delivery (0%) were similar to, or less than, that
expected in the general population. In the second publication from this data
source, case reports from 31 women with first trimester exposure to formoterol
were identified; 8% of infants had major congenital anomalies, 10% of preg-
nancies ended in spontaneous abortion, and 20% of infants were born preterm.
Although some of these figures are greater than what would be expected, the num-
ber of exposed maternal–infant pairs is small, and there is no formal compari-
son group.
Table 3
Summary of selected studies on long-acting b2 agonist medications
Percent
Investigators with event
[ref] Design Source of subjects No. of subjects End points or P value
Wilton Cohort UK Prescription 91 salmeterol Congenital anomalies 2%
et al [14] event monitoring 65 exposed Spontaneous abortion 8%
1st trimester Preterm delivery 0%
liveborn
Wilton & Cohort UK Prescription 31 formoterol Congenital anomalies 8%
Shakir [15] event monitoring Spontaneous abortion 10%
Preterm delivery 20%
Bracken Cohort Practice/clinic 2141 unexposed Low birth weight NS
et al [13] based U.S. 48 exposed Preterm delivery NS
northeast 64 exposed
Abbreviation: NS, not significant.
The MFMU study included 77 salmeterol-exposed subjects; outcomes were

not reported separately from short-acting b2 agonists, but as a group, no increased
risks were associated with all b2 agonists combined [10]. Similarly, Bracken and
colleagues [13] reported no increased risk for preterm delivery in 64 pregnancies
with exposure to long-acting bronchodilators (OR, 1.69; 95% CI, 0.76–3.77), and
no increased risk for low birth weight among 48 exposed asthmatic women
(OR, 1.10; 95% CI, 0.39–3.11), compared with unexposed asthmatic and non-
asthmatic women combined.
Oral corticosteroids
In contrast to generally reassuring data about most older asthma medications,

the data on oral corticosteroids (Table 4) have raised some concerns. In the 1997
cohort study by Schatz and colleagues [8], among 130 women who were exposed
to oral, but not inhaled, steroids, rates of preeclampsia (13.2% versus 7.5%,
P = .022) and low birth weight (8.5% versus 3.4%, P =.005) were increased
compared with unexposed controls. In multivariate analysis, the association of
oral steroids with preeclampsia persisted (adjusted OR, 2.0; 95% CI, 1.11–3.61).
In the MFMU cohort study [10], the rate of preterm delivery was significantly
higher in 185 oral steroid users compared with 1938 unexposed asthmatic
women, even after adjustment for demographic and disease severity confounders
(OR, 1.54; 95% CI, 1.02–2.33); the prevalence of low birth weight also was
increased (OR, 1.80; 95% CI, 1.13–2.88). Although rates of major malformations
were similar between exposed and unexposed women (2.2% versus 2.0%), small
cohort studies such as this have limited power to detect anything other than high
relative risks for this particular outcome.
These findings were replicated in the study of northeastern U.S. clinics by
Bracken and colleagues [13], in which the odds of preterm delivery were in-
creased among 52 women who used oral steroids relative to all other pregnancies
(OR, 3.37; 95% CI, 1.66–6.86). In multivariate analysis, with each additional
dose per month, the odds of preterm delivery increased by 11% (adjusted
OR, 1.11; 95% CI, 1.03–1.18). This translated to a reduction in gestational age of
2.2 weeks in women who used oral steroids daily across pregnancy. No increased
risk was noted for low birth weight among 26 women who were exposed to oral
steroids in the same study.
Four large case-control studies have implicated oral steroids with respect to
risk for a specific major birth defect—oral clefts. The first, drawn from the
Hungarian population-based birth defects surveillance study, reported a signifi-
cantly elevated OR for oral steroid use in the first month of pregnancy (adjusted
OR for cleft lip with or without cleft palate 5.9; 95% CI, 1.7—20.3) [16].
Maternal use of steroids was reported in this study for a variety of indications,
only 25% of which were asthma. No adjustment was made for maternal smoking,
which is an independent risk factor for clefts; and the OR estimate was based on
three cases of affected and exposed infants.
20 chambers
Table 4
Summary of selected studies on oral corticosteroids
P value
Investigators or OR
[ref] Design Source of subjects No. of subjects End points (95% CI)
Schatz Cohort
U.S. hospital/clinic- 1364 unexposed Low birth weight NS
et al [8] based Southwest 130 exposed Preterm delivery NS
Preeclampsia Adj. OR 2.0
(1.1–3.6)
Schatz Cohort U.S. multicenter 1938 unexposed Congenital NS
Low birth weight Adj OR 1.8
(1.1–2.9)
Preterm delivery Adj OR 1.5
(1.0–2.3)
Bracken Cohort Practice/clinic- 2153–2175 Low birth weight NS
et al [13] based U.S. unexposed Preterm delivery Adj. OR 1.1
northeast 26 exposed (1.0–1.2)
52 exposed
Czeizel & Case- Hungary 20,800 Cleft lip F cleft Adj. OR 5.9
Rockenbaver control malformed palate (1.7–20.3)
[16] 35,700 controls
Rodriguez- Case- Spain 24,000 Cleft lip F cleft Adj. OR 6.6
Pinilla & control malformed palate (1.4–29.8)
Martinez- 11,100 controls Cleft palate
Frias [17]
Carmichael & Case- California 662 cases Cleft lip F cleft OR 4.3
Shaw [18] control 734 controls palate (1.1–17.2)
Cleft palate OR 5.3
(1.1–26.5)
Pradat Case- International 645 cases Cleft lip F cleft OR 2.59
et al [19] control ~11,000 mal- palate (1.18–5.67)
formed controls
Park-Wyllie Cohort Teratogen 188 unexposed Congenital NS
et al [20] Information 187 exposed anomalies
Service Canada Lower birth P b.001
weight
Preterm delivery P b.001
Abbreviations: Adj, adjusted; NS, not significant.
The second study, which was published in 1998 by Rodriguez-Pinilla and

Martinez-Frias [17], reported data from a hospital-based case-control study in
Spain. Significantly elevated ORs for oral clefts (cleft palate and cleft lip with
or without cleft palate) were associated with any corticosteroid use in the first
trimester compared with normal and malformed controls (adjusted OR,
6.6; 95% CI, 1.4–29.8). These estimates were based on five exposed cases, three
of which were multiply malformed; no information was provided on the indi-
cation for treatment.
The third study was derived from data collected by the California Birth
Defects Monitoring Program, in which significantly elevated ORs were noted for
isolated cleft lip with or without cleft palate (OR, 4.3; 95%, CI 1.1–17.2) and
isolated cleft palate (OR, 5.3; 95% CI, 1.1–26.5) in association with oral steroid
use in the 3-month period around conception [18]. These estimates were based on
nine exposed cases, one of which involved maternal asthma; no adjustment was
made for confounders.
The fourth study, a recent update from nine malformation registries that
contribute to the Malformation Drug Exposure Surveillance database [19], also
reported a statistically significant increased risk for cleft lip with or without cleft
palate with systemic corticosteroid use (OR, 2.59; 95% CI, 1.18–5.67). This
estimate was based on seven exposed cases with no information about indication
for use and no adjustment for confounders.
In contrast, cohort studies have not shown a statistically significant increased
risk for overall malformations or oral clefts alone with systemic steroid use in
pregnancy. A meta-analysis that was conducted recently by Park-Wyllie and
colleagues [20] summarized six published cohort studies, and came to a simi-
lar conclusion regarding the risk for all malformations combined (OR, 1.45;
95% CI, 0.81–2.60). Even with aggregated data from these cohort studies, only
535 exposed pregnancies could be included; this sample size is far too limited to
examine risk for oral clefts alone. In this same meta-analysis, the summary OR
derived from case-control studies was statistically significant with an estimate of
3.35 (95% CI, 1.97–5.69) for oral clefts in association with systemic steroid use
around the first trimester.
Thus, if the association between systemic steroid use and oral clefts is causal,
and if the risk applies equally when oral steroids are used to treat asthma as well
as any other condition, the best estimate of the risk is that for every 1000 women
who take oral steroids during the critical period in embryonic development, the
risk may be increased from a baseline of about one per 1000 to approximately
three affected infants per 1000 exposed.
Inhaled corticosteroids
Several recent studies addressed the risks that are associated with prenatal
exposure to inhaled steroids (Table 5). In a cohort study drawn from a perinatal
database in Nova Scotia, Alexander and colleagues [21] reported on 139 steroid-
exposed pregnancies. Users of inhaled steroids were not distinguished from oral
steroid users; nevertheless, in comparison with 678 asthmatic women and 13,709
nonasthmatic controls, no increased risks were shown for major congenital
anomalies overall (adjusted relative risk [RR], 0.8; 95% CI, 0.4–1.7), low birth
weight (adjusted RR, 1.0; 95% CI, 0.4–2.5), or preterm delivery (adjusted RR,
1.4; 95% CI, 0.6–3.0). A relative risk of borderline significance was shown for
pregnancy-induced hypertension (adjusted RR, 1.7; 95% CI, 1.0–2.9).
In the 1997 study by Schatz and colleagues [8], only a small number of
women were exposed to inhaled steroids without concomitant exposure to oral
steroids (n= 64). Compared with approximately 1428 asthmatic and nonasthmatic
unexposed women, no significant increased risks were noted for preeclampsia,
22 chambers
Table 5
Summary of selected studies on inhaled corticosteroids
P value or
Source of OR (95% CI)
Investigators Design subjects No. of subjects End points or rate ratio
Alexander Cohort Perinatal database 13,709 controls Congenital Adj. OR 0.8
et al [21] Nova Scotia 678 asthmatic anomalies (0.4–1.7)
unexposed Low birth Adj. OR 1.0
139 asthmatic weight (0.4–2.5)
steroid (any) Preterm Adj. OR 1.4
exposed delivery (0.6–3.0)
PIH Adj. OR 1.7
(1.0–2.9)
Schatz Cohort U.S. multicenter 2123 asthmatics Congenital NS
Low birth NS
weight
Preterm NS
delivery
Preeclampsia/ NS
PIH
Namazy Cohort Allergists U.S. 474 exposed Congenital Comparable
et al [22] American College/ No controls malformations to population
AAAAI Low birth rates
weight
Preterm
delivery
Kallen Cohort Swedish Medical Concurrent Congenital Rate ratio 1.1
et al [23] birth register population anomalies
comparison
2014 exposed
to budesonide
Norjavaara & Cohort Swedish medical Concurrent Mean birth P b.05a
de Verdier birth register population weight
[24] comparison Stillbirth NS
2968 exposed Preterm P b.05b
to budesonide delivery
Bracken Cohort Practice/clinic- 2029–2065 Low birth Adj. OR 1.0
et al [13] based U.S. unexposed weight (0.9–1.1)
northeast 176 exposed Preterm Adj. OR 1.0
136 exposed delivery (1.0–1.0)
Abbreviations: AAAAI, American Academy of Asthma, Allergy and Immunology; Adj, adjusted;
PIH, pregnancy-induced hypertension.
a
Mean difference in birth weight for girls exposed to budesonide early in pregnancy relative to
all girls 40 grams; mean difference in birth weight for boys with early pregnancy exposure to
budesonide 20 grams.
b
Mean difference in gestational age for boys exposed to budesonide early in pregnancy relative
to all boys is 0.2 weeks; no difference for girls.
preterm birth, or low birth weight. In the more recent MFMU study, 722 subjects
were exposed to inhaled steroids, most commonly beclomethasone, followed by
triamcinolone. Rates of major malformations, preterm delivery, low birth weight,
and gestational hypertension were equal to or less than rates for these same
outcomes in the unexposed asthmatic comparison group [10].
Similar findings were reported from another cohort study that was conducted
by allergists across the United States through the American College of Allergy,
Asthma and Immunology and the American Academy of Asthma, Allergy and
Immunology [22]. Among 474 inhaled-steroid users who were enrolled in the
study, no increased incidence of low birth weight, preterm birth, or congenital
malformations was noted compared with expected rates in the general population;
however, no control group was recruited as part of this study.
Exposure to the specific inhaled steroid, budesonide, in 2014 infants who were
born to asthmatic women was evaluated by Kallen and colleagues [23] using data
from the population-based Swedish Medical Birth Register cohort study. Com-
pared with all other pregnancy outcomes, the risk ratio for all major congenital
anomalies combined was 1.1 (3.8% versus 3.5%). Four infants were born with
oral clefts (risk ratio, 1.2; 95% CI, 0.3–3.1), but this number not substantially
in excess of expected numbers. Again, this larger cohort study lacks sufficient
power to rule out risks for specific malformations, such as oral clefts. Therefore,
this question remains unanswered.
The same Swedish population-based resource was used by Norjavaara and
de Verdier [24] to examine risks for low birth weight, stillbirth, and preterm
delivery. With 2968 budesonide-exposed pregnancies, no significant excess of
stillbirths was noted compared with women who used other asthma drugs or
nonasthmatics. Although slightly smaller adjusted mean birth weights were noted
among girls ( 40 g) and boys ( 20 g) with early exposure to budesonide relative
to all others, these differences were similar to those found among infants whose
mothers used asthma drugs other than budesonide. Furthermore, infants who
were born to women who continued to use budesonide throughout pregnancy
had slightly higher mean birth weights compared with nonasthmatic controls.
With respect to gestational age, the findings were similar, with an approximately
1 to 2 days average shortened gestational age among boys with early or
late pregnancy exposure to budesonide. The investigators concluded that ex-
posure to budesonide was not linked to any clinically relevant effect in this
large study.
Cromolyn
Limited recent data are available on the safety of cromolyn in pregnancy. In

the 1997 cohort study by Schatz and colleagues [8], 151 first-trimester users were
enrolled (including inhaled, intranasal, and ophthalmic); no significant increased
risk for birth defects overall was noted (6.0% versus 5.0%, P N.05). Similarly, in
191 women who were prescribed cromolyn in the Michigan Medicaid claims
24 chambers
database, no excess of major anomalies was seen [11]. In the MFMU study, only
60 women were enrolled with cromolyn exposure; although no significant
differences were seen in any perinatal outcome measured, power was limited
[10]. In crude analysis, a significant excess of preterm deliveries was noted
among 22 cromolyn users in the study by Bracken and colleagues [13]; however,
after adjustment for confounders in multivariable analysis, the association was no
longer significant (adjusted OR, 1.01; 95% CI, 0.98–1.03). In the same study, no
increased risk for low birth weight was found among 18 exposed subjects.
Leukotriene modifiers
This new class of drugs has limited published human data available regarding
pregnancy safety. Fewer than 10 exposed pregnancies were enrolled in the cohort
that was studied by Bracken and colleagues [13]; this provided limited power to
assess the risk for preterm delivery or low birth weight in that study. A pregnancy
registry is being maintained for montelukast by the drug manufacturer. As of
July, 2004, 151 prospectively ascertained pregnancies have been completed, of
which 116 involved first-trimester exposures. Seven major malformations were
reported in this group [25]. The data on leukotriene modifiers are too limited to
draw any conclusions.
Medications used for the treatment of rhinitis in pregnancy
Antihistamines
Data from the Collaborative Perinatal Project and several generally small
human studies have contributed some knowledge about the safety of older or
first-generation antihistamines, including chlorpheniramine, triprolidine, tripe-
lennamine, and hydroxyzine, none of which has been associated with an in-
creased risk for major congenital malformations [12,26]. A few studies have
suggested an increased risk for overall birth defects for selected antihistamines,
including brompheniramine [12], diphenhydramine [27], and promethazine [28];
however, at least as many studies have contradicted these findings for major birth
defects overall [12,29].
The second-generation antihistamines were introduced only recently; there-
fore, little data have been published on the use of these medications in preg-
nancy. One small cohort study of 33 cetirizine-exposed pregnancies, published
by Einarson and colleagues [30], noted no increased risk for major birth defects
compared with outcomes in 38 unexposed pregnancies. Another small cohort
study by Pastuszak and colleagues [31] focused on astemizole; they found no
increased risk of major birth defects in infants of 114 exposed women compared
with infants of 114 unexposed controls.
The Swedish Medical Birth Register data was used by Kallen [32] to evaluate
pregnancy outcome with early exposure to a broad range of antihistamines, in-
cluding clemastine (n=1230), deschlorpheniramine (n=226), alimenazine (n=35),
cetirizine (n= 917), terfenadine (n =1164), loratadine (n= 1769), and fexofenadine
(n= 16). No significant increased risks were found for preterm delivery, low birth
weight, perinatal death, or all malformations when these medications were used
early in pregnancy to treat allergy. Among women who used loratadine, about
twice as many male infants were born with hypospadias than would be expected
from the general population rates.
Another cohort study, conducted by Diav-Citrin and colleagues [33] and pub-
lished in 2003, compared pregnancy outcome among 210 women who were
exposed to loratadine (77.9% in the first trimester) with 267 women who were
exposed to other antihistamines and 929 women who were not exposed to
either. No significant differences were found between groups regarding major
anomalies overall, preterm delivery, or birth weight. At the same time, a study
that involved four centers was published by Moretti and colleagues [34]. This
study compared 161 first trimester loratadine-exposed pregnancies with a simi-
lar number of unexposed women. No differences were found in overall mal-
formations, gestational age, or mean birth weight; no infant in the exposed group
had hypospadias. A further evaluation of hypospadias risk in association with
loratadine was performed in the U.S. National Birth Defects Prevention Study
case control setting [35]. In 563 male infants who had hypospadias and
1444 male infant controls, the adjusted OR for loratadine exposure was 0.96
(95% CI, 0.41–2.22), and showed no association between the exposure and this
particular malformation.
Decongestants
Among the decongestants, phenylephrine has been associated with an in-

creased risk for birth defects in the Collaborative Perinatal Project and one
other case-control study [14,36]; however, other studies have not confirmed this
association [30]. Pseudoephedrine, as a vasoactive medication, has been linked to
some major birth defects that are believed to have a vascular disruptive etiology
(eg, gastroschisis and small intestinal atresia). Werler and colleagues [36] found
an OR of 1.8 (95% CI 1.0–3.2) for early pregnancy exposure to pseudoephedrine
among 206 patients who had gastroschisis compared with 798 nonmalformed
controls. This association was accentuated when the product used also contained
acetaminophen (OR, 4.2; 95% CI, 1.9–9.2); a similar pattern of associations was
found for small intestinal atresia. Although the link between this decongestant
and gastroschisis has been reported in several studies, it is still unclear if this is a
causal relation. If it is—because defects like gastroschisis are so rare and occur in
perhaps two or three infants per 10,000 births—the absolute risk is small. For
every 10,000 women who are exposed to pseudoephedrine early in pregnancy,
an estimated two or three additional children would be affected over and above
the two or three that would be expected.
26 chambers
Intranasal allergy medications
In addition to oral decongestants, Werler and colleagues [37] examined the

association between intranasal decongestants, including oxymetazoline, xylometa-
zoline, tetryzoline, nephazoline, and phenylephrine, and the risk for gastroschisis.
Although the number of exposed women was small for each medication, no
statistically significant association was found between these agents and the
defect. There is limited pregnancy outcome information in the literature on the
use of intranasal steroids or intranasal cromolyn. Although it is not clear how
the absorbed dose of these medications, delivered in this manner, compares with
an inhaled form of the same drug, pregnancy safety information on these medi-
cations, when used in the inhaled form, may provide some information.
Summary
Given the unique nature of pregnancy with respect to obtaining safety data
regarding medication exposures, developing comprehensive information on the
wide variety of medications that might be of clinical benefit during pregnancy is a
challenging and on-going task. For many of the most commonly used asthma and
allergy medications that were covered in this article, there is at least limited
human data are available. Even for relatively well-studied medications, there are
many unanswered questions, and few studies exist that are large enough to rule
out at least a doubling of risk for specific outcomes, particularly congenital
anomalies. This challenge becomes even more daunting when evaluating risks of
individual products is considered the optimal goal, as opposed to ‘‘lumping’’ all
medication exposures within a class. All of these issues call for more human
pregnancy data that are collected more efficiently so that the answers that cli-
nicians and pregnant women need are available more readily.
In the meantime, health care providers and pregnant women must work with
the information that is available to evaluate the risks and benefits of a particu-
lar medication and alternative choices for treatment of asthma or allergy during
pregnancy, while considering the potential for adverse effects if the woman
with severe or uncontrolled asthma is under-treated. To assist in making a
risk/benefit assessment, the clinician can draw on existing resources that pro-
vide systematic periodic review of new data on medications in pregnancy as it
becomes available, and synthesize the entire body of data on a particular drug
into concise summary statements. Two such resources are TERIS (Teratogen
Information System) [38] and Reprotox [39]; both on-line services are managed
by experts in the field of teratology. An additional resource for clinicians and
pregnant women is the Organization of Teratology Information Specialists [40], a
network of risk-assessment counselors in the United States and Canada who
specialize in research and the communication of risks that are associated with
exposures in pregnancy.
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26 (2006) 29 – 62
The Epidemiology of Asthma During

Pregnancy: Prevalence, Diagnosis,
and Symptoms
Helen L. Kwon, PhDa, Elizabeth W. Triche, PhDb,
Kathleen Belanger, PhDb, Michael B. Bracken, PhDb,T
a
Department of Epidemiology, Mailman School of Public Health, Columbia University,
722 West 168th Street, 7th Floor, New York, NY 10032, USA
b
Yale Center for Perinatal, Pediatric and Environmental Epidemiology,
Department of Epidemiology and Public Health, Yale University School of Medicine,
One Church Street, 6th Floor, New Haven, CT 06510, USA
Asthma is reported to be the most common obstructive pulmonary disease of

pregnancy and one of the most common serious medical conditions to complicate
pregnancy [1,2]. Trends in asthma prevalence in the United States have increased
over the past several decades, particularly among younger age groups, which
suggests a concurrent increase in prevalence in the pregnant population [3,4]. We
previously demonstrated from U.S. national health surveys that the prevalence
of asthma during pregnancy in 1997 to 2001 was between 3.7% (95% CI,
2.7%–4.7%) and 8.4% (95% CI, 7.1%–9.8%) [5].
This article provides an overview of the most current national and interna-
tional trends in the epidemiology of asthma during pregnancy. We begin by using
several recent national health surveys to update our previous estimates of the
prevalence of ever having received a diagnosis of asthma by a health pro-
fessional, and current asthma, among pregnant women and women of child-
bearing age in the United States. Trends in these estimates over time are
examined, and markers of asthma control are described by population character-
istics. A summary of international estimates of asthma in pregnancy is provided.
This work was supported with grants AI41040 and DA05484 from the National Institutes of
Health and the Kellogg Scholars in Health Disparities Program.
E-mail address: michael.bracken@yale.edu (M.B. Bracken).
30 kwon et al
We also review some potential problems in the validity of asthma diagnoses and
conclude with a description of reported asthma symptoms and medication use in
pregnancy from a large ongoing prospective study.
Asthma prevalence
Prevalence of asthma during pregnancy in the United States
Data sources
The National Health Interview Survey (NHIS) is a cross-sectional survey,
which is planned and conducted in conjunction with the U.S. Bureau of the
Census. Since its inception in 1957, the NHIS has been the primary source of
general health information on the civilian, noninstitutionalized population of the
United States, and the primary source of asthma prevalence data in the non-
pregnant population of the United States [6]. A 1997 survey redesign added
questions about asthma that inquired explicitly about physician-diagnosed
asthma, asthma attacks in the past 12 months, and visits to an emergency room
or urgent care center because of asthma in the past 12 months. Women 18 to
49 years of age were asked about their current pregnancy status. In 2001, a ques-
tion about current asthma was added that allows comparability to other national
surveys that inquire about asthma. In 2003, the response rate for total households
was 89.2% and for adults was 77.3%.
The National Health and Nutrition Examination Survey (NHANES), ad-
ministered by the National Center for Health Statistics (NCHS), is a national
probability sample of the civilian, noninstitutionalized population of the United
States. In addition to a home interview, NHANES includes medical and dental
examinations, physiologic measurements, and laboratory tests performed by
trained medical personnel in Mobile Examination Centers [7]. Beginning in 1999,
NHANES became a continuous, annual survey rather than a periodic survey.
Survey data are released every 2 years for public use. The overall response rate
for NHANES II (1976–1980) was 73% and for NHANES III (1988–1994) was
79% [7,8]. For 1999–2000, the overall interview response rate was 82% and the
examined response rate was 78%.
The Behavioral Risk Factor Surveillance System (BRFSS), a collaboration
between the Centers for Disease Control and Prevention and U.S. states and
territories, is a random-digit–dialed telephone survey of one adult per household
that has collected uniform, state-specific data of the adult population 18 years of
age or older since 1984 [9]. Poststratification adjustment of BRFSS data, which
forces the sum of the weighted frequencies to equal population estimates for each
region or state, enables nationally representative estimates to be produced. By
1996, 50 states, the District of Columbia, Puerto Rico, and the Virgin Islands
were participating in BRFSS. In 2000, questions about pregnancy and asthma
were added to the core component of the questionnaire [10]. In 2003, the median
epidemiology of asthma during pregnancy 31
survey response rate among U.S. states and territories was 53.2% (ranging from
34.4% in New Jersey to 80.5% in Puerto Rico) [11].
Assessment of pregnancy and asthma

Table 1 describes the questions on pregnancy and asthma from the 2001–2003
NHIS, 2000–2003 BRFSS, NHANES III (1988–1994), 1999–2000 NHANES,
and 2001–2002 NHANES. Because of an unusually low response rate to the
question about current asthma in the 1999–2000 NHANES, most of the analyses
that involve NHANES focus on the 2001–2002 NHANES. Markers of asthma
control, including asthma attacks and asthma-related emergency visits, were
evaluated from the 1997–2003 NHIS. Asthma attacks were assessed among those
who reported an asthma diagnosis with the question, ‘‘During the past 12 months,
have you had an episode of asthma or asthma attack?’’. Among those who
reported an asthma attack, asthma-related emergency visits were considered with,
‘‘During the past 12 months, have you had to visit an emergency room or urgent
care center because of asthma?’’.
Data analysis
In our analysis, women of childbearing age were defined as 18 to 44 years of
age. Women who were unsure or refused to answer the questions about their asthma
were excluded from all analyses; women who were unsure or refused to answer
the questions about pregnancy were excluded from analyses of pregnant women.
To increase comparability between surveys, weighted state-specific BRFSS
data were aggregated and subsetted to exclude Puerto Rico, Guam, and the Virgin
Islands. Data from multiple years were combined to increase the precision of
estimates. Estimated numbers of U.S. women and prevalence rates with 95%
confidence intervals were calculated from the 2000–2003 BRFSS and 2001–2003
NHIS for ever having received an asthma diagnosis and current asthma among
pregnant women and women of childbearing age. Trends over time among
women of childbearing age were examined using NHANES II, NHANES III, and
the 2001–2002 NHANES. Because of small numbers among population sub-
groups, data were combined from the 1997 to 2003 NHIS surveys to describe
asthma control by various demographic characteristics. Prevalence estimates for
asthma attacks and asthma-related emergency visits were calculated. Weighted
prevalence estimates and standard errors for all datasets were calculated using
SUDAAN, a statistical software package that is used to account for the complex
survey design and to adjust for selection probability, oversampling, and non-
response. In keeping with NCHS standards, estimates were considered statisti-
cally unreliable and not reported if the relative standard was greater than 30%. All
analyses were performed using SAS Version 9.1 (SAS Institute, Cary, North
Carolina) and SUDAAN Release 9.0 (RTI, Chapel Hill, North Carolina).
Estimates of asthma prevalence

We derived estimates of the prevalence of asthma in pregnant and all child-
bearing-aged women from the following unweighted numbers of women 18 to
32
Table 1
Comparison of Centers for Disease Control and Prevention and National Center for Health Statistics surveys for estimation of the prevalence of asthma during pregnancy
Survey Years Pregnancy measurement Asthma measurement
National Health Interview Survey 1957–2003a 1997–2003: 1957–1967:
(2003: N=30,852) ‘‘Are you currently pregnant?’’ ‘‘Now ITm going to read a list of conditions—Please
(Women 18–49 years) tell me if you, your ___, etc., have had any of these
conditions during the past 12 months? Asthma?’’
1970:
‘‘Now ITm going to read a list of conditions; During
kwon et al
the past 12 months, did anyone in the family have

any of these conditions— . . .Asthma?’’ and ‘‘Who
was this?’’
1978–1996:
‘‘During the past 12 months, did anyone in the family
have— . . .Asthma?’’ and ‘‘Who was this?’’
1997–2000:
‘‘Have you ever been told by a doctor or other
health professional that you have asthma?’’ and
‘‘During the past 12 months, have you had an
episode of asthma or asthma attack?’’
2001–2003:
‘‘Have you ever been told by a doctor or other
health professional that you have asthma?’’ and
‘‘Do you still have asthma?’’
National Health and Nutrition NHANES I: 1970–1975 1970–1975, 1976–1980: 1970–1975:
Examination Survey (NHANES) (N=31,973) ‘‘Are you pregnant now?’’ ‘‘Has a doctor ever told you that you have had any
NHANES II: 1976–1980 1988–1994: of the following conditions: asthma?’’ and ‘‘Do you
(N=27,801) ‘‘Have you ever been pregnant?’’ still have it?’’
NHANES III: 1988–1994 and ‘‘Are you now pregnant?’’ + 1976–1980:
(N=39,695) positive urine pregnancy test ‘‘Did a doctor ever tell you that you had any of the
NHANES 1999–2000 (20–59 years) following conditions, and if so, do you still have
(N=9,965) 1999–2002: it? . . .Asthma? Still have it?’’
NHANES 2001–2002 ‘‘Have you ever been pregnant?’’ 1988–1994:
(N=11,039) and ‘‘Do you think you are ‘‘Has a doctor ever told you that you had asthma?’’
pregnant now?’’ + positive urine and ‘‘Do you still have asthma?’’
pregnancy test (Women 15–49 1999–2002:
years [1999–2000]; Women 12–60 ‘‘Have you ever been told by a doctor or other
[2001–2002]) health professional that you have asthma?’’ and
‘‘Do you still have asthma?’’
Behavioral Risk Factor 1994–2003a 2000–2003: 2000: ‘‘Did a doctor ever tell you that you had
Surveillance System (2001: N=264,684) ‘‘To your knowledge, are you asthma?’’ and ‘‘Do you still have asthma?’’
now pregnant?’’ 2001–2003: ‘‘Have you ever been told by a doctor,
(Women 18–44 years with nurse, or other health professional that you had
intact cervix) asthma?’’ and ‘‘Do you still have asthma?’’
a
Data available annually for this period.
epidemiology of asthma during pregnancy
33
34 kwon et al
44 years of age: 233,161 in the 2000–2001 BRFSS, 64,564 in the 1997–2003 NHIS,
and 1622 in the 2001–2002 NHANES. The weighted proportion of current
pregnancy among all women aged 18 to 44 ranged from 4.4% in the 2001–2003
NHIS to 8.7% in the 2001–2002 NHANES.
As shown in Table 2, the number of women 18 to 44 years of age who ever
received a diagnosis of asthma from a health professional in the United States is
estimated to range between 6.8 and 7.4 million—12.3% (95% CI, 11.9%–12.8%)
and 13.7% (95% CI, 13.4%–13.9%) of childbearing-aged women in the 2001–
2003 NHIS and the 2000–2003 BRFSS, respectively. Among pregnant women
18 to 44 years of age, approximately 233,607 to 300,151 women, or 12.4% (95%
CI; 11.2%–13.8%) of pregnant women in the 2000–2003 BRFSS and 12.6%
(95% CI, 10.4%–15.2%) of pregnant women in the 2001–2003 NHIS have re-
ceived a diagnosis of asthma. Age-specific rates of ever having received a diag-
nosis are slightly lower among pregnant women 25 to 44 years of age compared
with all childbearing-aged women 25 to 44 years of age, but are comparable or
slightly higher among pregnant women 18 to 24 years of age compared with all
childbearing-aged women 18 to 24 years of age.
Table 2 also describes the prevalence of current asthma among women 18 to
44 years of age. An estimated 4.6 to 5.1 million women in the United States
annually, or 8.4% (95% CI, 8.0%–8.8%) and 9.5% (95% CI, 9.3%–9.7%) of
childbearing-aged women in the 2001–2003 NHIS and the 2000–2003 BRFSS,
respectively, reported current asthma. Among pregnant women 18 to 44 years of
age, 157,648 to 209,396 women, or 8.4% (95% CI, 7.4%–9.5%) of pregnant
women in the 2000–2003 BRFSS and 8.8% (95% CI, 7.0%–11.0%) of pregnant
women in the 2001–2003 NHIS, had current asthma. Age-specific rates of current
asthma are lower among pregnant women 25 to 44 years of age compared with all
childbearing-aged women 25 to 44 years of age, but are comparable or slightly
higher among pregnant women 18 to 24 years of age compared with all child-
bearing-aged women 18 to 24 years of age. Among women 18 to 24 years of age,
12.2% (95% CI, 9.9%–14.9%) and 12.3% (95% CI, 8.6%–17.3%) of pregnant
women in the 2000–2003 BRFSS and the 2001–2003 NHIS, respectively, re-
ported current asthma.
A slightly higher estimate (14.7%; 95% CI, 8.0%–25.6%) of pregnant woman
who ever had received a diagnosis of asthma came from the 2001–2002 NHANES
(Table 3). The results from the 1999–2000 NHANES are slightly higher, although
the confidence intervals are wide and overlap between 1999–2000 and 2001–
2002. We were unable to estimate current asthma among pregnant women from
the 2001–2002 NHANES because of the small sample size.
Trends in asthma prevalence over time

Trends over time in asthma prevalence among women of childbearing age
(18–44 years of age) were analyzed using NHANES II, NHANES III, and 2001–
2002 NHANES, and among pregnant women using NHANES III and 2001–2002
NHANES (see Table 3). As reported previously [5], between 1976 to 1980 and
1988 to 1994, the prevalence of ever having received a diagnosis of asthma
Table 2
Estimated annual asthma prevalence among pregnant and childbearing-aged women, 18 to 44 years of age—United Statesa, Behavioral Risk Factor Surveillance System,
National Health Interview Survey, 2000–2003
All women Pregnantb women
c d
Asthma diagnosis, ever Current asthma Asthma diagnosis, ever Current asthma
e
N % 95% CI N % 95% CI N % 95% CI N % 95% CI
BRFSS, 2000–2003
Total 7,366,349 13.7 13.4–13.9 5,096,260 9.5 9.3–9.7 233,606 12.4 11.2–13.8 157,649 8.4 7.4–9.5
Age (y)
18–24 2,093,504 16.0 15.4–16.6 1,382,044 10.6 10.1–11.1 113,270 17.3 14.6–20.3 79,671 12.2 9.9–14.9
25–34 2,503,808 13.3 12.9–13.6 1,718,761 9.1 8.8–9.4 99,421 10.2 8.9–11.6 64,768 6.7 5.7–7.8
35–44 2,769,037 12.6 12.3–13.0 1,995,455 9.1 8.8–9.4 20,915 8.3 5.8–11.8 13,210 5.3 3.5–7.8
NHIS, 2001–2003
Total 6,808,207 12.3 11.9–12.8 4,643,947 8.4 8.0–8.8 300,151 12.6 10.4–15.2 209,396 8.8 7.0–11.0
Age (y)
18–24 1,960,531 14.3 13.2–15.5 1,331,320 9.7 8.8–10.8 121,408 14.9 10.9–20.1 99,644 12.3 8.6–17.3
25–34 2,293,586 12.0 11.3–12.8 1,528,246 8.0 7.4–8.7 135,596 10.9 8.3–14.3 86,359 7.0 5.0–9.6
35–44 2,554,090 11.4 10.7–12.1 1,784,381 8.0 7.4–8.6 43,147 13.2 8.5–19.9 23,393 7.1 4.0–12.5
a
Includes the 50 states and the District of Columbia.
b
Answering ‘‘yes’’ to ‘‘To your knowledge, are you now pregnant?’’ (BRFSS, 2000–2003) or ‘‘Are you currently pregnant?’’ (NHIS, 2001–2003).
c
Answering ‘‘yes’’ to ‘‘Did a doctor ever tell you that you had asthma?’’ (BRFSS, 2000), or ‘‘Have you ever been told by a doctor, nurse, or other health professional
that you had asthma?’’(BRFSS, 2001–2003), or ‘‘Have you ever been told by a doctor or other health professional that you have asthma?’’ (NHIS, 2001–2003).
d
Answering ‘‘yes’’ to ‘‘Do you still have asthma?’’ (BRFSS, 2000–2003 and NHIS, 2001–2003).
e
Estimated annual number for the United States.
35
36
Table 3
Estimated annual asthma prevalence among pregnant and childbearing-aged women, 18 to 44 years of age—United Statesa, National Health and Nutrition Examination
Survey, 1976–2002
c d
Asthma diagnosis, ever Current asthma Asthma diagnosis, ever Current asthma
Ne % 95% CI N % 95% CI N % 95% CI N % 95% CI
1976–1980
Total 2,617,268 6.0 4.6–7.4 1,262,827 2.9 2.0–3.8 —f —
Age (y)
kwon et al
18–24 670,658 4.7 3.5–5.9 262,020 1.8 0.9–2.7 — —

25–34 1,100,326 6.6 4.4–8.7 568,924 3.4 1.9–4.9 — —
35–44 846,284 6.9 4.7–9.1 431,883 3.5 2.1–5.0 — —
1988–1994
Total 4,175,236 7.6 6.7–8.6 3,128,966 5.7 4.8–6.7 201,557 6.6 2.7–10.4 98,580 3.2 1.6–4.9
Age (y)
18–24 1,001,649 7.6 5.4–9.7 795,093 6.0 4.0–8.0 — —
25–34 1,546,868 7.5 5.5–9.6 1,236,343 6.0 4.0–8.0 — —
35–44 1,626,719 7.8 6.3–9.2 1,097,530 5.3 4.0–6.5 — —
1999–2000
Total 8,643,055 15.1 12.0–19.0 —g 749,757 16.2 9.8–25.7 —
Age (y)
18–24 2,212,721 15.7 10.3–23.4 — — —
25–34 3,376,912 16.2 12.2–21.2 — 316,245 12.0 8.1–17.5 —
35–44 3,053,422 13.8 11.1–17.0 — — —
2001–2002
Total 8,621,412 15.2 11.7–19.5 5,117,307 9.0 6.6–12.2 680,871 14.7 8.0–25.6 —
Age (y)
18–24 2,251,525 15.6 10.4–22.9 1,301,635 9.0 5.7–14.1 — —
25–34 2,964,937 14.3 9.2–21.4 1,839,723 8.9 4.6–16.3 — —
35–44 3,404,950 15.7 12.2–20.1 1,975,949 9.2 6.6–12.6 — —
a
Includes the 50 states.
b
Answering ‘‘yes’’ to ‘‘Are you pregnant now?’’ (1976–1980), or ‘‘yes’’ to ‘‘Have you ever been pregnant?’’ and ‘‘Are you now pregnant?’’ + positive urine
pregnancy test (1988–1994), or ‘‘yes’’ to ‘‘Are you currently pregnant?’’ or a positive urine pregnancy test (2001–2002).
c
Answering ‘‘yes, still have it,’’ ‘‘yes, does not still have it,’’ ‘‘yes, blank but applicable,’’ or ‘‘yes, don’t know if still have it’’ to ‘‘Did a doctor ever tell you that you
had any of the following conditions, and if so, do you still have it?’’ (1976–1980), or ‘‘yes’’ to ‘‘Has a doctor ever told you that you had asthma?’’ (1988–1994), or ‘‘yes’’
to the question, ‘‘Have you ever been told by a doctor or other health professional that you had asthma?’’ (2001–2002).
d
Answering ‘‘yes, still have it’’ to ‘‘Did a doctor ever tell you that you had any of the following conditions, and if so, do you still have it?’’ (1976–1980), or ‘‘yes’’ to
the questions, ‘‘Has a doctor ever told you that you had asthma?’’ and ‘‘Do you still have asthma?’’ (1988–1994), or ‘‘yes’’ to the questions, ‘‘Have you ever been told by a
doctor or other health professional that you had asthma?’’ and ‘‘Do you still have asthma?’’ (2001–2002).
e
Estimated annual number for the United States.
f
Too few observations to calculate reliable estimates.
g
Estimate seems to be unreliable because of unusually low response to question ‘‘Do you still have asthma?’’ in the 1999–2000 survey cycle.
37
38
Table 4
Estimated annual prevalence of asthma control characteristics among pregnant and childbearing-aged women, 18 to 44 years of age—United Statesa, National Health
Interview Survey, 1997–2003
Asthma attackc ED visitd Asthma attack ED visit
% 95% CI % 95% CI % 95 % CI % 95% CI
Total 5.0 4.8–5.3 1.4 1.3–1.5 4.1 3.4–5.1 1.6 1.2–2.2
Age (y)
kwon et al
18–24 5.4 5.0–5.9 1.7 1.4–2.0 5.4 3.9–7.5 1.9 1.2–3.0

25–34 4.9 4.6–5.3 1.4 1.2–1.6 3.5 2.5–4.8 1.5 0.9–2.5
35–44 4.9 4.6–5.2 1.3 1.1–1.4 3.4 1.9–5.9 —e
Marital status
Married 4.2 4.0–4.5 1.0 0.9–1.1 3.1 2.4–4.0 1.2 0.7–1.9
Unmarried 6.0 5.7–6.4 1.9 1.8–2.2 7.1 5.0–10.0 2.8 1.8–4.3
Family income
b$20,000 6.5 6.1–6.9 2.4 2.2–2.7 5.6 4.0–7.7 2.5 1.6–3.9
$20,000 4.7 4.5–5.0 1.2 1.0–1.3 3.9 3.0–5.1 1.5 0.9–2.2
Race/ethnicity
Hispanic or Latinof 4.5 4.1–4.9 1.2 1.0–1.4 3.9 2.7–5.8 2.1 1.3–3.5
Puerto Rican 10.9 9.2–12.9 4.8 3.7–6.3 18.2 9.9–31.2 —
Mexican 1.8 1.3–2.4 0.6 0.4–1.0 — —
Mexican American 2.8 2.2–3.6 0.9 0.6–1.3 — —
Other Hispanic 3.6 3.0–4.3 1.2 0.9–1.5 — —
Black, non-Hispanic 4.6 4.2–5.1 1.9 1.6–2.3 4.1 2.4–7.1 —
White, non-Hispanic 5.4 5.2–5.7 1.4 1.3–1.6 4.5 3.4–5.9 1.4 0.9–2.3
Other, non-Hispanicg 3.4 2.7–4.2 0.8 0.5–1.3 — —
Regionh
Northeast 5.5 5.0–5.9 1.8 1.5–2.1 6.4 4.3–9.2 3.1 1.8–5.5
Midwest 5.5 5.1–5.9 1.4 1.2–1.6 3.7 2.4–5.4 —
South 4.4 4.1–4.8 1.2 1.1–1.4 4.3 3.0–6.3 1.8 1.1–3.0
West 5.3 4.8–5.8 1.4 1.2–1.6 2.7 1.6–4.3 —
Abbreviation: ED, emergency department.
a
Includes the 50 states and the District of Columbia.
b
Answering ‘‘yes’’ to ‘‘Are you currently pregnant?’’.
c
Answering ‘‘yes’’ to ‘‘Have you ever been told by a doctor or other health professional that you have asthma?’’ and ‘‘During the past 12 months, have you had an
episode of asthma or asthma attack?’’.
d
Answering ‘‘yes’’ to ‘‘Have you ever been told by a doctor or other health professional that you have asthma?’’, ‘‘During the past 12 months, have you had an
episode of asthma or asthma attack?’’, and ‘‘During the past 12 months, have you had to visit an emergency room or urgent care center because of asthma?’’.
e
Estimate considered unreliable because relative standard error N30%.
f
Women of Hispanic or Latino origin may be of any race or combination of races.
g
Includes other race or combination of races.
h
Northeast = Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Pennsylvania, Rhode Island, and Vermont; Midwest = Illinois, Indiana,
Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, Ohio, South Dakota, and Wisconsin; South = Alabama, Arkansas, Delaware, District of
Columbia, Florida, Georgia, Kentucky, Louisiana, Maryland, Mississippi, North Carolina, Oklahoma, South Carolina, Tennessee, Texas, Virginia, and West Virginia; and
West = Alaska, Arizona, California, Colorado, Hawaii, Idaho, Montana, Nevada, New Mexico, Oregon, Utah, Washington, and Wyoming.
39
40 kwon et al
increased from 6.0% (95% CI, 4.2%–7.9%) to 7.6% (95% CI, 5.7%–9.5%)
among women of childbearing age, whereas the prevalence of current asthma
doubled from 2.9% (95% CI, 1.6%–4.2%) to 5.7% (95% CI, 4.8%–6.7%).
Among the youngest age group (18–24 years of age), the prevalence of current
asthma more than tripled from 1.8% (95% CI, 0.9%–2.7%) to 6.0% (95% CI,
4.0%–8.0%). Between 1988 to 1994 and 2001 to 2002, the prevalence of ever
having received a diagnosis of asthma doubled to 15.2% (95% CI, 11.7%–
19.5%), whereas the prevalence of current asthma increased to 9.0% (95% CI,
6.6%–12.2%).
Among pregnant women, between 1988 to 1994 and 2001 to 2002, the preva-
lence of ever having received a diagnosis of asthma more than doubled from
6.6% (95% CI, 2.7%–10.4%) to 14.7% (95% CI, 8.0%–25.6%) (see Table 3). We
were unable to assess trends in current asthma over time in pregnant women
because of the small sample size of the 2001–2002 NHANES.
Estimates of asthma control during pregnancy

As demonstrated in Table 4, the estimated annual prevalence of self-reported
asthma attacks by pregnant women in the United States is 4.1% (95% CI, 3.4%–
5.1%). Thus, an estimated 98,164 of 254,970, or 38.5% (95% CI, 32.2%–45.3%)
of pregnant women with an asthma diagnosis in the United States reported having
experienced at least one asthma attack in the previous year. The prevalence of
asthma attacks seems to be elevated among pregnant women who are younger,
unmarried, or have a lower annual family income. Puerto Rican women, in
particular, are much more likely than other Hispanic subgroups or racial/ethnic
groups to report an asthma attack in the previous year. As Figs. 1 through 5
demonstrate, however, the effect of race/ethnicity differs by marital status and
income; unmarried and lower income white, non-Hispanic women who are preg-
16 15.2
14.7
14
12
10
Percent
1976-1980
8 7.6 1988-1994
6.6 2001-2002
6
6
0
All women Pregnant women
Fig. 1. Trends over time in asthma prevalence among pregnant and childbearing-age women,
18–24 years of age—United States, National Health and Nutrition Examination Survey.
16
14
12
10
Percent
Unmarried
8
Married
0
Puerto Rican Mexican Mexican- Other Hispanic Black, non- White, non- Other race, non-
American Hispanic Hispanic Hispanic
Fig. 2. Asthma attack prevalence among childbearing-age women, 18–24 years of age by race/
ethnicity and marital status—United States, National Health Interview Survey, 1997–2003.
nant have a higher prevalence of asthma attacks than do pregnant Hispanics overall.
In addition, the prevalence of asthma attacks among married pregnant women
(3.1%; 95% CI, 2.4%–4.0%) is slightly lower than the rate among married
childbearing-aged women overall, whereas the attack prevalence of 7.1% (95% CI,
5.0%–10.0%) is slightly higher. There seems to be some variation in the asthma
attack prevalence by geographic region of residence within the United States.
16
14
12
10
Percent
<$20,000
8
$20,000+
0
Puerto Rican Mexican Mexican- Other Hispanic Black, non- White, non- Other race, non-
American Hispanic Hispanic Hispanic
ethnicity and family income—United States, National Health Interview Survey, 1997–2003.
42 kwon et al
10
6
Percent
Unmarried
5
Married
0
Hispanic Black, non-Hispanic White, non-Hispanic
ethnicity and marital status—United States, National Health Interview Survey, 1997–2003.
Table 4 also shows that the estimated annual prevalence of self-reported

emergency visits for asthma by pregnant women in the United States is 1.6%
(95% CI, 1.2% – 2.2%). Thus, an estimated 37,990 of 98,164, or 38.7% (95% CI,
28.9% – 49.5%) of pregnant women who have experienced at least one asthma
attack in the previous year report having had to visit an emergency room or
urgent care center because of asthma during that year. The prevalence of asthma
emergency visits seems to be elevated among pregnant women who are younger,
5
Percent
<$20,000
4
$20,000+
0
Hispanic White, non-Hispanic
Fig. 5. Asthma attack prevalence among pregnant women, 18–24 years of age by race/ethnicity and
family income—United States, National Health Interview Survey, 1997–2003.
unmarried, of lower income status, of Hispanic or Latino heritage, or live in the

northeast United States.
Prevalence of asthma during pregnancy internationally
We assessed recent international reports of asthma in pregnancy. An electronic

search was conducting with MEDLINE/PUBMED (1990 to August 2005) using
the search strategy: asthma and (pregnancy or pregnant). Studies were included
that assessed whether pregnant or recently delivered women had ever had asthma
or currently had asthma. Studies were not excluded on the basis of language or on
the basis of providing a nationally representative sample. Results are summarized
in Table 5 [12–22]. Estimates of current asthma during pregnancy ranged from
0.4% from hospital discharge data that were collected for administrative purposes
in Canada between 1989 and 1996, to 12.4% of pregnant women in Western
Australia, where asthma prevalence in the general population is much higher.
Differences in definitions of asthma, time periods, and populations assessed may
have contributed to the wide geographic variation that was observed. Interna-
tional studies of children and adults using standardized definitions for assessing
asthma within a shared time frame demonstrated striking differences in asthma
prevalence throughout the world [23,24]. Differences in genetic, social,
environmental, and health care context that are experienced by pregnant women
across settings also may contribute to international variations in the prevalence of
Conclusions on prevalence
Data from the most recent U.S. national health surveys demonstrate that the
prevalence of current asthma during pregnancy is between 8.4% (BRFSS, 95%
CI; 7.4%–9.5%) and 8.8% (NHIS, 95% CI, 7.0%–11.0%). The prevalence seems
to be increasing, as indicated by increasing prevalence among younger pregnant
women in these data, as well as increasing trends over time in women of
childbearing age in NHANES. The addition of a question about current asthma to
the 2001 NHIS allowed us to estimate the prevalence of asthma in a comparable
manner to the BRFSS and to consider asthma attack prevalence separately, as a
marker of asthma control.
The estimated annual prevalence of self-reported asthma attacks by pregnant
women in the United States is 4.1% (95% CI, 3.4%–5.1%). Hence, an estimated
98,164 of 254,970, or 38.5% (95% CI; 32.2%–45.3%) of pregnant women with an
asthma diagnosis in the United States report having experienced at least one
asthma attack in the previous year. An estimated 37,990 of 98,164, or 38.7% (95%
CI; 28.9%–49.5%) of pregnant women who experienced at least one asthma attack
in the previous year report having had to visit an emergency room or urgent care
center because of asthma during that year. Thus, a substantial portion of pregnant
asthmatics seem to be experiencing significant asthma-related morbidity.
44
Table 5
International estimations of the prevalence of asthma during pregnancy
Author, year, country Study design Participants Asthma measurement Results
Alexander et al, 1998 Retrospective cohort All women residing in Halifax County, Current asthma identified from 5.6% current asthma
[12], Canada Nova Scotia, who delivered at Grace perinatal database using a (increase from 4.8% in
Maternity Hospital between diagnostic code for asthma 1991 to 6.9% in 1993)
January 1, 1991 and December 31,
1993 (N=14,565)
Kurinczuk et al, 1999 Cross-sectional Ten percent random sample of recently Ever asthma: ever having had 21.3% ever asthma,
[13], Australia delivered Western Australian mothers three or more attacks of wheezing 12.4% current
selected from the MidwivesT Notification at any stage in life provided that asthma, 8.8% asthma
of Birth Forms received by the Health the attacks did not occur only in attack or wheezing
Department of Western Australia who the first year of life during pregnancy
delivered between January 1 and Current asthma: having been told
April 16, 1995, surveyed by postal by a doctor that they had asthma
questionnaire (N=635) and the asthma was reported as still
kwon et al
continuing, or having had an attack

of wheezing or asthma in the past
year (ie, during their pregnancy)
Elleg3rd et al, 2000 Prospective cohort Pregnant women at their first visit at five Self-reported asthma recorded by 6.5% current asthma
[14], Sweden antenatal care centers in the southern part an interviewing midwife during
of a Swedish county (N=599) first prenatal visit
K7llén et al, 2000 Retrospective cohort Women in the Swedish Medical Birth Self-reported asthma recorded by an 3.8% current asthma
[15], Sweden Registry of births from all delivery units interviewing midwife during first
in Sweden between 1984 and 1995 prenatal visit and ever having been
(N=36,985) hospitalized for asthma (from
hospital discharge register)
Wen et al, 2001 Retrospective cohort Women admitted to the hospital for Current asthma defined as having a 0.43% current asthma
[16], Canada obstetric delivery as reported by the discharge diagnosis of asthma
Canadian Institute for Health for (ICD-9 code of 493) in any of the
1989–1990 to 1995–1996 (N=2,017,553) first eight diagnosis fields
Pereira et al, 2002 Case series All pregnant adolescents (16 y old) History of asthma from chart review 2.5% ever asthma
[17], Mexico who attended the Coordination for the
Attention of the Teenage Patient of the
National Perinatology Institute who
delivered between June 1998 and
May 1999 (N=296)
Bager et al, 2003 Prospective cohort Singleton women born in Denmark Ever asthma: ever had asthma and, 11.4% ever asthma,
[18], Denmark between 1973–1977 (aged 20 to 28 y) if so, whether it had been diagnosed 6.6% current asthma
recruited during their first prenatal visit by a doctor
with their general practitioners as part Current asthma: ever asthma and
of the Danish National Birth Cohort reported that they still had asthma
Study and interviewed between 1997
and 2000 (N=9,722)
Karmaus and Eneli, Cross-sectional Pregnant women admitted to maternity Self-reported doctor-diagnosed asthma 2.5% ever asthma
2003 [19], Germany wards in six regions in Germany as
part of the European Studies on Infertility
and Subfecundity (N=1318)
Frey et al, 2004 Prospective cohort Women recruited from two maternity Self-reported doctor-diagnosed asthma 13% ever asthma
[20], Switzerland hospitals in Berne, Switzerland,
interviewed a few days after birth
(N=105)
Miyake et al, 2005 Cross-sectional Pregnant women from Negyagawa and Asthma after the age of 18: any 4.7% asthma after
[21], Japan other municipalities recruited for the asthma medication use after 18 y age 18, 2.1%
baseline survey of the Osaka Maternal and of age current asthma
Child Health Study between November 1, Current asthma: any asthma drug use
2001 and March 31, 2003 (N=1,002) in the previous 12 mo
Westergaard et al, 2005 Cross-sectional Pregnant women in the Danish National Ever asthma: ever had asthma and, 8.4% ever asthma
[22], Denmark Birth Cohort from September 29, 1997 if so, whether it had been diagnosed
to March 14, 2000 (N=31,145). by a doctor
Abbreviation: ICD-9, International Classification of Diseases, Ninth Revision.
45
46 kwon et al
We found that this burden did not seem to be shared evenly across population
subgroups. The prevalence of asthma attacks and asthma-related emergency visits
was elevated among pregnant women who were younger, unmarried, of lower
income, or of Puerto Rican or non-Hispanic black background (in the case of
asthma-related emergency visits). We were unable to sort out the complex rela-
tionships between race/ethnicity and socioeconomic status and health care use
behavior, or to demonstrate whether the effects of a characteristic (eg, marital
status) reflects the influence of access to material resources, socioeconomic po-
sition, the presence or absence of social support, or other factors.
Despite the paucity of international data on asthma in pregnancy and the lack
of consistency in study design and measurement of asthma between studies, we
were able to demonstrate some of the international variation in asthma preva-
lence. Further work with nationally representative data is needed to characterize
better the international trends in asthma during pregnancy.
Understanding national and international epidemiologic trends in asthma
during pregnancy is relevant to the clinician and researcher. Continued develop-
ments in the epidemiology of asthma during pregnancy will provide the context
for further understanding of disease etiology as well as improvement in the pre-
vention and management of this widely prevalent condition. Refer to Box 1 for a
summary of asthma prevalence.
Box 1. Summary: asthma prevalence
Asthma was estimated to affect between 157,648 and 209,396

pregnant women in 2000 to 2003, or approximately 8.4% to 8.8%
of pregnant women in the United States.
Between 1988 to 1994 and 2001 to 2002, the prevalence of
ever having been diagnosed with asthma among pregnant U.S.
women increased from 6.6% to 14.7%.
Approximately 4.1% of pregnant women in the United States
report having had an asthma attack in the previous year.
A substantial proportion of pregnant women with an asthma
diagnosis, 38.5%, report having had an asthma attack in the pre-
vious year, and 38.7% of women with an asthma attack report
having had to visit an emergency room or urgent care center be-
cause of their asthma.
Pregnant women who were younger, unmarried, of lower in-
come, Puerto Rican, or lived in the northeast United States ex-
perienced more asthma attacks or asthma-related emergency visits
during the previous year.
International studies demonstrate wide variations in asthma
prevalence during pregnancy; further characterization of interna-
tional trends is needed.
Asthma diagnosis
How valid are survey data on asthma prevalence?
Survey prevalence data are heavily dependent on the diagnosis of asthma by a

doctor or health professional (see Table 1). Other studies that use chart review,
administrative databases, or medical records also frequently depend on clinical
diagnoses and other information that requires an encounter with the health care
system. We are unaware of specific studies that examined diagnostic validity in
pregnant women; however, it is likely that issues in diagnosing asthma in non-
pregnant women are similar and are reviewed briefly below.
Underdiagnosis of asthma
Prevalence of asthma is estimated from national surveys in which women are

asked, ‘‘Have you ever been told by a doctor or other health professional that you
have asthma?’’ (emphasis added). The accuracy of these estimates relies on the
validity of the asthma diagnosis at any point in the subject’s life, but particularly
during childhood; the validity and reliability of asthma diagnosis in the com-
munity; and whether the diagnosis was communicated to, and understood by, the
patient. Rather than taking these factors into account, investigations of under-
diagnosis of asthma usually compare asthma symptoms that are reported on
questionnaires with reports of diagnosis on the same questionnaire.
There has been concern that minority children and children in poverty may be
less likely to be diagnosed with asthma because of the lack of access to ap-
propriate health care. Akinbami and colleagues [25] examined this possible bias
in the National Health Interview Survey. The analysis included children ages 3 to
17 years. Among children who wheezed in the past 12 months, minority children
were more likely to have an asthma diagnosis. After controlling for severity of
symptoms, 56.9% of white children who wheezed had an asthma diagnosis,
compared with 70.5% of black non-Hispanic children, 82.8% of Puerto Rican
children, and 65.4% of Mexican children. Similarly, children from low-income
families who wheezed were more likely to be diagnosed than were those from
middle income families.
The relationship of asthma diagnosis in children to socioeconomic status also
was investigated in Sheffield, United Kingdom [26]. A survey was conducted of
all 8- and 9-year-old school children using the International Study of Asthma and
Allergies in Children (ISAAC) questionnaire. Social deprivation was based on
postal code and divided into quintiles. Among 637 children who reported ‘‘sig-
nificant asthma symptoms,’’ 383 (60.1%) reported no physician diagnosis; this
proportion did not vary across social status. Asthma symptoms were more
prevalent among more socially deprived children, and asthma medication use in
the absence of physician diagnosis was more prevalent among the more socially
advantaged, which suggested some bias in the labeling of asthma.
48 kwon et al
Some investigators also identified gender differences in asthma diagnosis in

children; girls are less likely to be diagnosed with asthma than are boys, despite
having similar symptoms. In a national study in the United Kingdom [27], the
ISAAC protocol was used to measure wheezing and asthma diagnosis in a
representative sample of 12- to 14-year-olds. Wheeze in the past 12 months was
reported by 33.3% of respondents, and was more common in older children and
in girls (odds ratio, 1.14; 95% CI, 1.08–1.20). Asthma diagnosis was reported by
20.9% of children but was less common in girls.
In a school study in Denmark, girls also were more likely to have un-
diagnosed asthma [28]. In this study of 495 children, 292 were selected at ran-
dom and 203 were selected based on family history of asthma. Evaluation
included peak flow, spirometry, methacholine challenge, and exercise testing.
Subjects who had no asthma diagnosis but who had asthma symptoms and at
least one positive test were considered to be undiagnosed asthmatics. Among
those who had diagnosed asthma, 33% were girls, compared with 69% among
those who were undiagnosed. Other factors that were associated independently
with the underdiagnosis of asthma were low physical activity and high body
mass index (BMI).
Overdiagnosis of asthma
Despite the National Asthma Education and Prevention Program [29] recom-
mendations for assessment of lung function using peak flow or spirometry, in
clinical practice asthma often is diagnosed based solely on respiratory symptoms.
This may lead to overdiagnosis of asthma because respiratory symptoms in the
adult population may be related to chronic obstructive pulmonary disease or other
respiratory conditions.
In the United States, Macy and colleagues [30] used the Kaiser Permanente
database in San Diego County, California to identify adult asthmatics. All mem-
bers (18–64 years; mean age, 51 years) who had a hospital, emergency depart-
ment, or outpatient visit for asthma or two or more dispensed prescriptions of
asthma medication during 2001 were included (n = 12,315). Of these, 7460 were
considered to be low risk; 400 low-risk patients were selected randomly for
diagnostic evaluation. Asthma could be confirmed in only 62.2% (51/82) of the
subjects who completed the clinical and pulmonary function evaluation.
Similar evidence of overdiagnosis was reported from Halifax, Nova Scotia,
Canada [31]. Among 90 adults who were diagnosed as having asthma by a
physician, 41% had no evidence of reversible airflow obstruction, and had
negative methacholine challenge tests. Only 52.2% of subjects reported having
undergone any pulmonary function testing previously. Among subjects in whom
asthma was not confirmed, 62% were taking asthma medications.
Among 206 patients (mean age, 36 years) who were diagnosed with asthma
and referred to the Asthma Center at Toronto Hospital [32], 129 (62.6%) did not
have airway responsiveness on methacholine challenge tests. Of the patients who
did not have airway responsiveness, 62% were receiving medication and had a
Box 2. Summary: asthma diagnosis
There is evidence that asthma is under- and overdiagnosed in a

variety of countries and settings.
There is a suggestion that systematic bias in reporting may
occur differentially by ethnicity and socioeconomic status.
A lack of diagnostic validity may influence survey
prevalence data.
mean duration of medication use of 2 years. After specialist evaluation, 98 of

206 patients (47.6%) had confirmed asthma. This study was not population-
based, and referral to the Asthma Center may overrepresent patients who have
atypical presentations or treatment failures as compared to the general population
of asthmatics.
In Goteborg, Sweden, two population-based primary care practices were
studied; all adult patients who had an asthma consultation were eligible for an
extensive asthma evaluation [33]. Of 123 eligible adults, 86 attended and 57 (66%)
had an asthma diagnosis confirmed. Failure to confirm the diagnosis of asthma
was more common in women (36%) than in men (29%) and in patients who were
older than 50 years (47%).
In summary, no study has examined the validity of asthma diagnoses in
pregnant women specifically. Nonetheless, evidence from adults, in general, and
women of childbearing age, in particular, suggests that under- and overreporting
is a probable occurrence. Moreover, some systematic bias is likely with respect to
ethnicity and socioeconomic status. Much more research is required to investigate
the validity of asthma diagnoses, in general, and in pregnant women, in particular
(Box 2).
Symptoms and medication use
If asthma diagnoses have uncertain validity, is it possible to study asthma

symptoms and asthma medication use, and what is the relationship between
diagnosis, symptoms, and medication? Epidemiologic data on asthmatic pregnant
women is sparse; many studies provide information only on the diagnosis of
asthma, rather than on the frequency of symptoms and medication use related to
asthma. In this section, we describe data from the women who had physician-
diagnosed asthma from our cohort study that examined the effect of asthma and
medication use on pregnancy outcomes. Although the population is limited to the
northeastern United States, and may not be generalizable to other pregnant
asthmatic women, it provides some of the most comprehensive and detailed
information on symptom frequency, medication use, and emergency care among
asthmatic women in pregnancy.
50 kwon et al
Symptoms and medication use in the year before pregnancy
Asthma symptoms (wheeze, chest tightness, shortness of breath, or persistent

cough) are common in women who have physician-diagnosed asthma, before and
during pregnancy. Of 941 women studied, nearly 80% had at least one asthma
symptom—approximately two thirds had wheeze, shortness of breath, or chest
tightness, and nearly half had persistent cough—during the year before preg-
nancy (Table 6). White, African American, and Hispanic women had similar
frequencies of asthma symptoms, whereas women who were Asian or other race
had lower frequencies of all asthma symptoms. Younger, less educated women
were less likely to have asthma symptoms in the year before pregnancy, whereas
Table 6
Distribution of asthma symptoms in the year before pregnancy by selected population characteristics
among women with self-reported history of physician-diagnosed asthma
Percent with
Percent with shortness of Percent with Percent with
Population characteristic Na wheeze breath chest tightness persistent cough
Total population 941 67.3 69.7 62.2 46.5
Race
White 560 69.3b 72.7b 64.1 45.0c
African American 95 71.6b 74.5b 62.1 55.8c
Hispanic 234 63.7b 63.8b 60.9 48.7c
Asian/Other 46 52.2b 52.2b 46.8 34.8c
Age (y)
b 20 156 57.7b 61.3b 54.1b 42.6
20 – b25 165 64.8b 66.9b 59.8b 48.2
25 – b30 238 73.5b 73.3b 66.8b 52.3
30 – b35 239 70.7b 76.8b 67.6b 44.4
35 138 64.5b 54.0b 57.3b 41.7
Education
bHigh school 199 59.8b 63.6 54.8 47.0b
High school graduate 189 69.3b 71.3 66.1 51.6b
Some college 223 72.2b 74.7 63.7 52.5b
College graduate 167 72.5b 69.1 65.9 39.3b
NCollege graduate 158 62.7b 69.7 61.9 38.8b
BMI
Underweight 103 62.1b 68.9 65.0 47.6b
Normal 457 64.8b 67.8 59.5 39.9b
Overweight 132 68.2b 71.2 62.9 47.3b
Obese 240 74.6b 73.5 66.7 58.2b
Smoked in year before pregnancy
No 678 65.3b 68.4 60.5c 43.4b
Yes 257 72.4b 72.9 66.7c 54.3b
Pets kept in home
No 428 63.8b 65.4b 58.3b 45.9
Yes 508 70.3b 73.3b 65.6b 47.0
a
Totals may differ due to missing values.
b
c2 P b.05.
c
.05 P b.10.
those who smoked or kept pets in the home were more likely to have asthma
symptoms in the year before pregnancy. Increasing BMI was associated with
increasing frequency of wheeze and persistent cough.
Consistent with the episodic and variable nature of asthma, the number of
months during which a woman had symptoms in the past year ranged from 0 to
12 (Table 7). Most women (69%) had symptoms for less than 6 months during
the year, whereas 24% were symptomatic for 10 or more months. In contrast, a
smaller proportion of women (26%) took controller medications in the year
before pregnancy, and only 13% took them for 10 or more months.
Table 7
Distribution of asthma symptoms and controller medication use in year before pregnancy among
women with self-reported history of physician-diagnosed asthma
N %
Wheeze
None 306 32.7
1–3 mo 255 27.2
4 – 6 mo 161 17.2
7–9 mo 57 6.1
10 or more mo 158 16.9
Shortness of breath
None 281 30.3
1–3 mo 268 28.9
4 – 6 mo 164 17.7
7–9 mo 52 5.6
10 or more mo 163 17.6
Chest tightness
None 352 37.7
1–3 mo 267 28.6
4 – 6 mo 146 15.6
7–9 mo 45 4.8
10 or more mo 124 13.3
Persistent cough
None 501 53.6
1–3 mo 219 23.4
4 – 6 mo 98 10.5
7–9 mo 28 3.0
10 or more mo 89 9.5
Any asthma symptom (wheeze or chest tightness or persistent cough)
None 197 21.0
1–3 mo 266 28.4
4 – 6 mo 184 19.6
7–9 mo 69 7.4
10 or more mo 221 23.6
Controller medication use
None 694 73.8
1–3 mo 87 9.2
4 – 6 mo 22 2.3
7–9 mo 19 2.0
10 or more mo 119 12.6
52 kwon et al
Frequency of symptoms was related to controller medication use in the year

before pregnancy; those who had more symptoms were more likely to use
controller medications (inhaled steroids, leukotriene inhibitors, cromones, the-
ophylline, long-acting b2 agonists, or systemic steroids). Most women in each
symptom frequency group, however, including those who had symptoms for at
least 10 months in the year, did not take controller medications. Only 22% of
women with 1 to 3 months of asthma symptoms, 31% with 4 to 6 months of
asthma symptoms, 52% with 7 to 9 months of asthma symptoms, and 42% with
10 or more months of asthma symptoms in the year before pregnancy reported
using any controller medication in that year.
Table 8
Average Global Initiative for Asthma treatment step in year before pregnancy by selected study
population characteristics among women with self-reported history of physician-diagnosed asthma
Average GINA treatment step in year before
Total pregnancy (%)
Population characteristic Na % 0 1 2 3 4
Total 941 100.0 38.7 42.2 12.7 4.1 2.3
Race
White 561 59.8 35.6b 40b 16.2b 5.2b 3.0b
African American 96 10.2 40.6b 43.8b 11.5b 1.0b 3.1b
Hispanic 235 25.0 42.1b 48.1b 6.4b 2.6b 0.8b
Asian/other 47 5.0 55.2b 36.2b 4.3b 4.3b 0.0b
Age
b 20 158 16.8 44.9b 50.7b 3.8b 0.6b 0.0b
20 – b 25 166 17.7 42.2b 44.6b 10.8b 1.2b 1.2b
25 – b 30 238 25.3 36.6b 39.5b 14.7b 4.2b 5.0b
30 – b 35 239 25.4 31.8b 43.6b 14.6b 7.5b 2.5b
N 35 139 14.8 43.9b 31.6b 17.3b 5.8b 1.4b
Education
bHigh school 201 21.4 43.3b 47.7b 6.5b 1.5b 1.0b
High school graduate 190 20.2 42.1b 42.1b 11.6b 2.6b 1.6b
Some college 223 23.7 39.0b 41.7b 13.9b 3.6b 1.8b
College graduate 168 17.9 33.3b 44.0b 13.1b 6.6b 3.0b
NCollege graduate 158 16.8 34.2b 33.5b 19.6b 7.6b 5.1b
BMI
Underweight 103 11.0 41.7 40.8 10.7 3.9 2.9
Normal 459 49.1 39.9 41.8 11.1 4.4 2.8
Overweight 132 14.1 43.9 40.9 11.4 3.0 0.8
Obese 242 25.8 32.6 44.2 16.5 4.6 2.1
Smoked in year before pregnancy
No 680 72.4 37.6 42.3 12.9 4.4 2.8
Yes 259 27.6 42.0 41.7 12.0 3.1 1.2
Pets kept in home
No 430 45.7 40.5 42.2 11.9 3.5 1.9
Yes 510 54.3 37.4 42.0 13.3 4.5 2.8
a
Totals may differ due to missing values.
b
c2 P b.05.
Most women in this population were not taking medications routinely to

control their asthma, and this was especially true for young, Hispanic, and less
educated women (Table 8). Only 19% of the study population had an average
Global Initiative for Asthma (GINA) treatment step of 2 or higher in the year
before pregnancy, a level that would indicate consistent, regular use of controller
medications. Nearly one quarter of white women, compared with 16% of African
American and 10% of Hispanic women, had an average treatment step of 2 or
higher. Similarly, a much larger proportion of women aged 25 and older, and
those who were well educated, used controller medications regularly during the
year before pregnancy.
Symptoms and medication use during pregnancy
Symptoms were equally common during pregnancy as before pregnancy in

this group of asthmatic women. Only 12% had no symptoms during pregnancy,
and 46% had an average GINA symptom step of 1, compared with 16% who
had symptoms almost daily across pregnancy (GINA symptom step of 3 or 4;
Table 9). Again, a much larger proportion (41%) of women did not take asthma
medications, especially controller medications, during pregnancy. Only 17% of
women had an average treatment step of 2 or higher (regular use of controller
medications) in pregnancy.
White and African American women were more likely to have moderate-
severe persistent asthma, on average, in pregnancy than were Hispanic or Asian/
other women (Table 10). A smaller percentage of younger women had moderate-
severe persistent asthma than did those who were 25 to 35 years old. Women who
smoked in pregnancy and those who kept pets in their homes were more likely to
have a higher average symptom step.
Table 9
Average and maximum Global Initiative for Asthma symptom and treatment steps across pregnancy
Average across pregnancy Maximum across pregnancy
N % N %
GINA symptom step
Step 0 – no symptoms 105 12.0 105 12.0
Step 1 403 46.3 114 13.1
Step 2 227 26.0 257 29.5
Step 3 104 11.9 152 17.4
Step 4 33 3.8 244 28.0
GINA treatment step
Step 0 – no medications 356 40.8 356 40.8
Step 1 372 42.6 303 34.8
Step 2 106 12.2 133 15.2
Step 3 28 3.2 59 6.8
Step 4 10 1.2 21 2.4
54 kwon et al
Table 10
Global Initiative for Asthma symptom and treatment steps averaged across pregnancy among women
with self-reported history of physician-diagnosed asthma (n = 941) in the Asthma in Pregnancy Study,
1996–2001
GINA symptom step (%) GINA treatment step (%)
Population characteristic 0 1 2 3 4 0 1 2 3 4
Total population 12.1 46.2 26.1 11.8 3.8 40.8 42.7 12.2 3.1 1.2
Race
White 10.2a 45.3a 25.7a 14.2a 4.6a 39.4 41.1 14.0 3.8 1.7
African American 13.0a 45.7a 22.8a 12.0a 6.5a 41.3 45.6 9.8 2.2 1.1
Hispanic 14.6a 47.9a 29.1a 7.5a 0.9a 41.3 47.4 9.9 1.4 0.0
Asian/other 20.4a 50.1a 20.4a 6.8a 2.3a 54.5a 34.1 6.8 4.6 0.0
Age
b20 14.4a 55.5a 22.6a 4.8a 2.7a 41.2a 50.6a 7.5a 0.7a 0.0a
20 to b25 12.3a 41a 31.8a 11.0a 3.9a 42.9a 45.5a 11.0a 0.0a 0.6a
25 to b30 11.6a 44.4a 27.6a 12.0a 4.4a 42.2a 38.7a 13.3a 4.9a 0.9a
30 to b35 11.2a 45.5a 22.8a 18.3a 2.2a 37.5a 42.4a 13.4a 5.4a 1.3a
35 11.5a 46.7a 26.2a 9.0a 6.6a 41.0a 38.5a 13.9a 3.3a 3.3a
Education
bHigh school 12.5b 50.5b 28.3b 4.9b 3.8b 40.2a 46.2a 12.0a 1.6a 0.0a
High school graduate 11.8b 45b 27.5b 12.9b 2.8b 43.4a 40.4a 14.0a 1.1a 1.1a
Some college 13.5b 37.9b 26.0b 16.8b 5.8b 42.8a 44.3a 8.6a 3.8a 0.5a
College graduate 13.5b 48.0b 23.1b 12.2b 3.2b 35.9a 47.7a 10.3a 3.8a 2.3a
NCollege graduate 8.3b 52.4b 24.1b 12.4b 2.8b 40.7a 33.8a 17.2a 6.2a 2.1a
BMI
Underweight 15.6 42.7 27.1 10.4 5.2 52.1a 30.2a 12.5a 3.1a 2.1a
Normal 12.6 50.5 23.6 11.0 2.3 42.2a 44.2a 8.7a 4.2a 0.7a
Overweight 11.5 45.9 29.5 9.8 3.3 35.2a 45.1a 16.4a 2.5a 0.8a
Obese 9.0 41.0 27.9 15.8 6.3 36.0a 44.2a 16.2a 1.8a 1.8a
First trimester smoking
No 12.4a 48.3a 25.2a 11.1a 3.0a 40.1 43.6 11.2 3.6 1.5
Yes 10.9a 38.9a 28.5a 15.0a 6.7a 44.0 38.9 15.0 2.1 0.0
Third trimester smoking
No 12.0b 48.2b 25.3b 11.7b 2.8b 40.3 42.9 11.8 3.7 1.3
Yes 10.8b 37.9b 29.7b 13.5b 8.1b 47.3 40.5 10.8 1.4 0.0
Pets kept in home
No 14.1a 48.9a 24.6a 8.9a 3.5a 42.4 44.5 10.2 2.2 0.7
Yes 10.3a 44.0a 27.1a 14.5a 4.1a 39.5 41.2 13.7 4.1 1.5
a
c2 P b.05.
b
.05 P b.10.
Younger women were less likely to take controller medications regularly than
were older women, and well-educated women were more likely to take them (see
Table 10). Women with normal BMI were less likely to take controller medi-
cations regularly in pregnancy than were overweight or obese women. Unlike in
the year before pregnancy, race was not associated with average treatment step
during pregnancy.
Although women who had more frequent symptoms in the year before
pregnancy were more likely to have a higher average symptom step in pregnancy,
approximately 75% of women who had no symptoms in the year before preg-
Table 11
Average Global Initiative for Asthma symptom and treatment steps across pregnancy by number
months of asthma symptomsa in year before pregnancy among women with self-reported history of
physician-diagnosed asthma
Number of months of asthma symptoms in year before pregnancy
None 1–3 mo 4 – 6 mo 7–9 mo 10+ mo
(n = 186) (n = 247) (n = 167) (n = 64) (n = 204)
% % % % %
Average GINA symptom step across pregnancy
No symptoms 25.8 15.4 6.6 1.6 2.9
Step 1 54.3 55.4 50.3 45.3 24.5
Step 2 14.5 22.3 30.5 28.1 36.8
Step 3 5.4 6.1 11.4 17.2 24.0
Step 4 0.0 0.8 1.2 7.8 11.8
Average GINA treatment step across pregnancy
No medication use 71.5 46.5 32.9 15.6 20.6
Step 1 25.3 46.2 50.3 54.7 43.6
Step 2 2.7 4.9 13.2 20.3 26.5
Step 3 0.0 2.0 3.6 7.8 5.9
Step 4 0.5 0.4 0.0 1.6 3.4
a
Asthma symptoms include: wheeze, shortness of breath, chest tightness, or persistent cough in
year before pregnancy (shortness of breath was not included in GINA categorization during pregnancy
because many pregnant women experience shortness of breath unrelated to respiratory function).
nancy had symptoms during pregnancy (Table 11). In contrast, nearly all women
who had symptoms for at least 4 months in the year before pregnancy had
symptoms during pregnancy; 35.8% of those who had symptoms for at least
10 months in the year before pregnancy had an average symptom step of 3 or 4
(daily symptoms) during pregnancy.
Few women who were asymptomatic during the year before pregnancy took
controller medications in pregnancy (see Table 11). Asthma treatment during
pregnancy was associated positively with months of symptoms during the year
before pregnancy. From 7.3% of women who had symptoms for 1 to 3 months
in the year before pregnancy to 35.8% of those who had symptoms for at least
10 months in the year before pregnancy had an average GINA treatment step of 2
Table 12
Use of asthma medications in pregnancy by average Global Initiative for Asthma symptom step across
pregnancy among women with self-reported history of physician-diagnosed asthma
Asthma medication use in pregnancy
Average GINA symptom No medication Rescue medication only 1+ controller medication

step across pregnancy N % N % N %
No symptoms 94 89.5 4 3.8 7 6.7
Intermittent 175 43.5 169 41.9 59 14.6
Mild persistent 66 29.1 81 35.7 80 35.2
Moderate persistent 19 18.3 36 34.6 49 47.1
Severe persistent 2 6.1 13 39.4 18 54.5
56 kwon et al
Box 3. Summary: asthma symptoms and medication use
Symptoms (wheeze, chest tightness, persistent cough) are

common before and during pregnancy among women who
have a diagnosis of asthma
80% had one or more symptoms in the year
before pregnancy
88% had one or more symptoms during pregnancy; 16%
had symptoms almost daily
Symptoms tended to be episodic before and during pregnancy
69% had symptoms for less than 6 months in the past year;
24% were symptomatic for at least 10 months
46% of women had an average GINA symptom step of 1
(intermittent) across pregnancy; 16% had symptoms
almost daily (average GINA symptom step of 3 or 4)
Asthma medication use before and during pregnancy was
much less common than were symptoms in these
asthmatic women
Only 26% took any asthma controller medication (inhaled
steroids, leukotriene inhibitors, cromones, theophylline,
long-acting C2 agonists, or systemic steroids) in the year
before pregnancy; 13% took controller medications for
at least 10 months in that year.
Even among women with 10 or more months of symptoms
in the year before pregnancy, only 42% reported using
any controller medication in that year.
Only 17% of the women took any controller medication
(average GINA treatment step of 2 or higher) regularly
in pregnancy.
Many asthmatic women who did not have symptoms in the
year before pregnancy had symptoms during pregnancy
75% of women who had no reported symptoms in the year
before pregnancy had symptoms during pregnancy
Nearly all women who had symptoms for at least 4 months in
the year before pregnancy had symptoms during pregnancy
Few women who were asymptomatic in the year before
pregnancy took controller medications in pregnancy
About half of women who took controller medications before
pregnancy took them during pregnancy
Only about half of women who had daily symptoms during
pregnancy took any controller medications in pregnancy
Table 13
Emergency room visits and hospitalizations in the year before and during pregnancy among women
with self-reported history of physician-diagnosed asthma
n %
Year before pregnancy
No ER visits or hospitalizations 658 88.9
ER visits, but no hospitalizations 65 8.8
Hospitalizations (F ER visits) 17 2.3
During pregnancy
No ER visits or hospitalizations 690 92.3
ER visits, but no hospitalizations 38 5.1
Hospitalizations (F ER visits) 12 1.6
Abbreviation: ER, emergency room.
or higher (controller medication use) during pregnancy. Only 3.5% of women

who did not take controller medications in the year before pregnancy took them
during pregnancy, compared with 58% of women who took controller medication
in the year before pregnancy.
Table 12 shows the association between asthma medication use during preg-
nancy and the frequency of symptoms during pregnancy. Women who had a
higher average symptom step during pregnancy were more likely to take one or
more controller medications during pregnancy; however, only approximately half
of the 137 women who had almost daily symptoms during pregnancy took any
controller medications in pregnancy (Box 3).
Emergent care for asthma
Approximately 11% of women had an emergency visit or hospitalization

for asthma in the year before pregnancy; 2% were hospitalizations (Table 13).
During pregnancy, 6.7% had emergent care for asthma, of which 1.6%
were hospitalizations.
Women who had asthma-related emergency care in the year before pregnancy
also were more likely to have emergency care during pregnancy (Table 14). Only
Table 14
Emergency room visits and hospitalizations during pregnancy by visits in the year before pregnancy
During pregnancy
No ER visits or ER visits, but no Hospitalizations
N hospitalizations (%) hospitalizations (%) (F ER visits) (%)
No ER visits or 658 95.2 4.0 0.8
hospitalizations
ER visits, but no 65 81.6 13.8 4.6
hospitalizations
Hospitalizations 17 58.8 17.7 23.5
(F ER visits)
58 kwon et al
Table 15
Global Initiative for Asthma treatment step in year before and during pregnancy by emergency room
visits and hospitalizations in the year before pregnancy among women with self-reported history of
physician-diagnosed asthma
No ER visits or ER visits, but no Hospitalizations
GINA treatment step hospitalizations (%) hospitalizations (%) (F ER visits) (%)
Step 0: No 42.5 6.6 13.6
asthma medications
Step 1: Rescue 41.7 46.1 45.4
medications only
Step 2: One 11.2 30.3 13.6
controller medications
Step 3: Two 3.3 10.5 9.1
controllers medications
Step 4: Three+ 1.4 6.6 18.2
During pregnancy
Step 0: No 43.2 17.8 25.0
asthma medications
Step 1: Rescue 43.2 42.5 30.0
medications only
Step 2: One 9.9 27.4 40.0
Step 3: Two 2.6 9.6 5.0
Step 4: Three+ 0.9 2.7 0.0
4.8% of women with no emergency department visits or hospitalization in the

year before pregnancy had an emergency department visit or hospitalization
during pregnancy, compared with 18.5% of those who had a previous emergency
department visit, and 41.2% of those who were hospitalized in the previous year.
Women who had earlier emergency room visits or hospitalizations were more
likely to have taken controller medications in the year before pregnancy (46%)
and during pregnancy (41%) than were women who had no emergent care
(~16%; Table 15). Nevertheless, 45% of these women took no controller medi-
cations at all in pregnancy, and more than half did not take them on a regular
basis (average treatment step of 2 or higher) before or during pregnancy.
Summary
We demonstrated that asthma remains a common condition among pregnant

women and that the prevalence of self-reported asthma in the United States is
between 8.4% and 8.8%. In addition, approximately 4.1% of all pregnant women
experienced an asthma attack in the previous year. Prevalence rates in other

countries seem to be higher or substantially lower; however, further characteri-
zation of international trends using nationally representative data is needed. Data
from a large prospective cohort study in the northeastern United States and national
data demonstrate continued opportunities for population-level improvement in
well-managed asthma during pregnancy. Finally, asthma diagnosis and asthma
control seem to differ by population characteristics (eg, age, race/ethnicity, socio-
economic status), and further research and clinical involvement are needed to ad-
dress potentially systematic variation in reporting and management of the disease.
Appendix 1. The Yale Asthma in Pregnancy Study: methods
We conducted a large, prospective cohort study of pregnant asthmatic and

nonasthmatic women to assess the association between asthma/asthma therapy on
birth outcomes. The study has been described in detail in previous publications
[34,35]. Pregnant women were recruited from 56 obstetric practices and 15
clinics associated with six participating hospitals in Connecticut and Massachu-
setts. More than 11,400 women were screened for eligibility between April 1997
and June 2000. Exclusion criteria included having insulin-dependent diabetes
mellitus, intending to terminate the pregnancy, not speaking English or Spanish,
or being more than 24 weeks’ gestation at enrollment. All women who had a self-
reported history of physician-diagnosed asthma (n= 1343) and a simple random
sample of 1.5 to 1 nonasthmatics (n= 2070) were invited to participate; a total of
2379 enrolled, of whom 941 had asthma. These 941 asthmatics provide infor-
mation on the characteristics of asthmatic women in pregnancy.
Detailed information on asthma symptoms and medication use in the year
before pregnancy and during pregnancy was collected using structured in-person
interviews at enrollment and post partum, and telephone interviews at 20, 28,
and 36 weeks’ gestation. This information was used to classify the severity of
women’s asthma during pregnancy according to a modification of the 2002
GINA guidelines [36]. GINA symptom and treatment steps were calculated for
each month of pregnancy, and were used to derive an average and maximum
symptom and treatment step across pregnancy. For the average GINA symptom
and treatment steps, monthly steps were averaged over the number of months of
pregnancy and rounded up to the next highest integer. Maximum symptom and
treatment steps were the highest step recorded during the pregnancy. Only
women who had singleton live births were classified according to these criteria.
Symptom steps were defined as follows:
Step 0: No symptoms during pregnancy

Step 1: Intermittent asthma: symptoms 1 to 7 days per month on average, or
nocturnal symptoms less than 2 nights per month
Step 2: Mild persistent asthma: symptoms more than 7 days but not every day
per month, or nocturnal symptoms 2 to 7 nights per month
60 kwon et al
Step 3: Moderate persistent asthma: symptoms daily, and nocturnal symptoms

less than 14 nights per month
Step 4: Severe persistent asthma: symptoms daily, and nocturnal symptoms at
least 14 nights per month
Asthma symptoms included self-reported wheeze, chest tightness or persis-

tent cough.
Treatment steps were defined as:
Step 0: No asthma medication use during pregnancy

Step 1: Intermittent. No daily controller medications; rescue medications used
as needed.
Step 2: Mild persistent. One controller medication (usually inhaled steroid).
Step 3: Moderate persistent. Two controller medications.
Step 4: Severe persistent. Three or more controller medications.
Asthma controller medications included systemic steroids, inhaled steroids,

long-acting b2-agonists, leukotriene inhibitors, cromones, and xanthine deriva-
tives (eg , theophylline).
Information on emergency visits and hospitalizations was obtained from
women at home interview and postpartum interview. Information on emergency
visits and hospitalizations during the year before pregnancy was obtained at the
initial home interview. In addition, a total of 740 of the 941 asthmatic women
with a singleton live birth completed a postpartum interview shortly after the
baby was born. At this interview, information on all emergency room visits and
hospitalizations during pregnancy was ascertained.
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26 (2006) 63 – 80
The Effect of Pregnancy on the

Course of Asthma
Joan C. Gluck, MDa,T, Paul A. Gluck, MDb
a
Florida Center for Allergy and Asthma Care and Research, 8970 S.W. 87th Court,
Miami, FL 33176, USA
b
Department of Obstetrics & Gynecology, University of Miami School of Medicine, Miami, FL, USA
Bronchial asthma is a chronic disease whose incidence and mortality increased

by more than 30% in the 1980s, with a threefold increase in women aged 18 to
24 years in the 1990s [1,2]. The course of bronchial asthma is one of exacerbation
and remission that is caused by a cascade of events. Airway inflammation (with
infiltration of inflammatory cells, such as eosinophils, lymphocytes and mast
cells) leads to increased airway responsiveness and airway obstruction. Multiple
intrinsic and extrinsic factors can influence the course of asthma, all of which
can occur concomitantly with pregnancy.
Asthma is the most common chronic pulmonary disease, and complicates ap-
proximately 4% to 8% of all pregnancies [2]. This percentage varies depending
on the specific questions that are used in surveys. The effect of pregnancy itself
on asthma has been evaluated in many studies over the years. The general
conclusion by Juniper and Newhouse [3], who used meta-analysis to evaluate
retrospective and prospective studies, is that one third of women have im-
provement of asthma during pregnancy, one third experience no change, and one
third have a worsening of their asthma. Severe asthmatics, even those under good
medical control before pregnancy, are more likely to experience severe exacer-
bations during pregnancy [4].
E-mail address: joancgluck@aol.com (J.C. Gluck).
64 gluck & gluck
Normal physiologic changes of pregnancy and their effects on asthma
There are many physiologic changes that occur during pregnancy. Some of
these could have beneficial effects on the course of asthma and others could be
deleterious (Box 1) [5]. The exact effects of these physiologic changes on the
course of asthma during pregnancy are unknown.
Respiratory tract
The impact on the respiratory tract is physical and functional during preg-
nancy. The diaphragm rises about 4 cm, the transverse diameter of the thoracic
cage increases about 2 cm, and the thoracic circumference increases about 6 cm.
There is a significant reduction in expiratory reserve volume and residual volume
of air in the lungs, especially in the last trimester. By term, there is a 17% to 25%
decrease in functional residual capacity [6].
Tidal volume, minute ventilatory volume, and minute oxygen uptake increase
substantially by the last trimester, although respiratory rate changes little (Table 1)
[7,8]. The most consistent respiratory change is an increase of almost 50% in
minute ventilation, which is caused by stimulation of the respiratory center by
increasing concentrations of progesterone [9]. Oxygen consumption increases
21% to 35% and peaks late in pregnancy [10].
Dyspnea occurs in 60% to 70% of pregnant women in the first and second
trimesters. This dyspnea is believed to be due to the increase in tidal volume that
lowers blood Pco2 and causes increased respiratory effort that is induced by
progesterone and estrogen. Pulmonary function is not impaired in normal preg-
nant women, but the sensation of dyspnea may cause apprehension and exacer-
bation in pregnant asthmatics. The decreased pulmonary reserve and increased
respiratory effort also may cause increased asthma [7].
The upper respiratory tract also is affected in pregnancy. Marked congestion
of the inferior nasal turbinates (stuffy nose of pregnancy) that lasts for at least
10 days and is not caused by viral infection or allergy was reported to occur in
22% to 72% of all pregnancies [11,12]. Symptoms begin most often during 20 to
22 weeks of gestation. Nearly all women improve by 2 to 4 weeks post partum.
A prospective study of 568 pregnant asthmatics showed a significant cor-
relation between the course of gestational asthma and the course of rhinitis during
pregnancy. In those patients who had less asthma during pregnancy, 51% had
fewer rhinitis symptoms, whereas 20% had increased rhinitis. Only 2% of pa-
tients whose asthma worsened reported less rhinitis, and 56% had increased
rhinitis. In patients whose asthma did not change during pregnancy, 27.5% had
increased rhinitis [13].
Gastroesophageal reflux
In asthma, reflux is associated with disease exacerbation, and medical and

surgical treatment of reflux has resulted in a decrease in asthma symptoms [14].
the effect of pregnancy on the course of asthma 65
Box 1. Physiologic changes during pregnancy that may affect the

course of asthma
Factors that may improve asthma
Progesterone-mediated bronchodilation
Decreased plasma-histamine–mediated bronchoconstriction
(due to increased circulating histaminase)
Estrogen- or progesterone-mediated potentiation of C-adrenergic
bronchodilation
Pulmonary effects of increased serum-free cortisol
Glucocorticosteroid-mediated increased C-adrenergic
responsiveness
Prostaglandin I2-mediated bronchial stabilization
Atrial natriuretic factor–induced bronchodilatation
Increased half-life or decreased protein binding of endogenous
or exogenous bronchodilators
Prostaglandin E–mediated bronchodilation (in the last 4 weeks)
Descent of fetus (in the last 4 weeks)
Factors that may worsen asthma
Pulmonary refractoriness to cortisol effects because of com-

petitive binding to glucocorticosteroid receptors by proges-
terone, aldosterone, or deoxycorticosterone
Prostaglandin F2B–mediated bronchoconstriction
Decreased functional residual capacity with resultant airway
closure during tidal breathing and altered ventilation-
perfusion ratios
Increased pulmonary capillary permeability
Increased upper airway resistance from nasal
turbinate congestion
Increased placental major basic protein reaching the lung
Increased viral or bacterial respiratory infections triggering
asthma exacerbations
Increased gastroesophageal reflux–induced asthma
Increased stress
Elevation of the diaphragm from the expanding uterus (in second
and third trimesters)
Modified from Schatz M. Asthma during pregnancy: interrelationships

and management. Ann Allergy 1992;68:123–33.
66 gluck & gluck
Table 1
Pulmonary function in pregnancy and postpartum
Function 10 week 24 week 36 week Postpartum
Respiratory rate (breaths/min) 15–16 16 16–17 16–17
Tidal volume (mL) 600–650 650 700 550a
Residual volume (L) 1.2 1.1 1.0 1.2a
Vital capacity (L) 3.8 3.9 4.1 3.8
a
Significant difference compared with pregnant state.
Data from Spatling L, Fallenstein F, Huch A, et al. The variability of cardiopulmonary adapta-
tion to pregnancy at rest and during exercise. Br J Obstet Gynaecol 1992;18:99(Suppl 8):99.
The increase in serum progesterone during pregnancy causes relaxation of the

smooth muscle in the lower esophageal sphincter, which results in reflux, heart-
burn, and indigestion in one third of all pregnancies [15,16]. This reflux could
exacerbate gestational asthma and may require treatment during pregnancy.
Hormonal changes
There are significant changes in estrogen and progesterone levels during

pregnancy. Progesterone levels increase at least 10-fold between the sixth and
thirty-sixth weeks of pregnancy. Estrogen levels also increase, with 100 times
more estradiol and 1000 times more estriol at term compared to nonpregnant
state. Progesterone levels decrease sharply immediately before delivery, and in-
crease uterine contractility.
Elevated progesterone reduces the contractility of smooth muscle in the uterus
[17]. It has not been shown that it has a similar effect on pulmonary smooth
muscle, but in the last 4 weeks of pregnancy, asthmatics have reduced wheezing,
sleep interference, and interference with activities [18].
Fetal effects
The fetus is antigenically foreign to the mother. An exchange of cells between

mother and fetus occurs in 10% to 20% of normal pregnancies. In view of this
exchange, an inappropriate response to fetal antigens could provoke increased
asthma [19]. In addition, emboli of placental trophoblasts are shed into the
maternal circulation from early pregnancy. These trophoblasts lodge in capillary
beds of the mother’s lungs, but the local response is unknown [20].
In an attempt to explain the variations in asthma course during pregnancy,
34 women who delivered a boy and a girl were studied by retrospective ques-
tionnaires [21]. The sex of the fetus did not affect the course of asthma in this
study. In contrast, in a prospective study, the women with female fetuses had
more asthma symptoms. Male fetuses produce a surge of androgens at weeks 12
to 16; this may be a factor in this interesting observation [21].
Course of asthma during pregnancy
Retrospective studies
It is important to recall that for many years, obstetricians and their patients
stopped all treatment as soon as pregnancy began. Asthma was not regarded as a
high-risk condition, so it is likely that more women had severe difficulty with
their asthma because of lack of treatment. In the 1966 edition of Williams
Obstetrics, the entire subject of asthma and pregnancy is discussed in just two
paragraphs [22]. Relying on one retrospective study [23], it stated that pregnancy
had no effect on asthma in most cases. No mention is made of any specific
problems with asthma during pregnancy or any specific treatment.
The changes in asthma symptoms during pregnancy were reported in several
retrospective (mostly case) studies from 1930 to 1967 [23–30]. In these studies of
25 or more women, comprising 1087 pregnancies, 36% had improved symptoms,
41% had unchanged symptoms, and 23% had worsened symptoms during preg-
nancy [6].
There was a marked difference in results from different investigators (Table 2).
There was a beneficial effect of pregnancy on asthma in from 3% to 50% of
patients. There was no effect in from 15% to 93% of patients, and an adverse
effect was reported in from 4% to 54% of patients. These subjects were found
by chart review [26,28,30,31] or by interview up to several years after their
pregnancy [23–25]. The changes in the course of asthma were determined by
reviewing medication requirements, symptoms, and hospitalizations.
Patients who were studied by Jensen [24], Gandevia [25], Gammal and
Warraki [28], Hiddlestone [31], and Williams [30] came from asthma or allergy
clinics. These clinics may have been biased toward women who had more
problematic asthma and included fewer mild asthmatics. For example, Jensen
[24] excluded 22 of (a potential) 106 women because their allergic disease was
quiescent during pregnancy. Because these patients came from asthma clinics,
Table 2
Effect of pregnancy on asthma: retrospective studies
First author (country) [ref] Improved (%) Same (%) Worse (%)
Jensen (Denmark) [24] 41 15 44
Gandevia (Australia) [25] 48 28 24
Turiaf (France) [26] 50 26 24
Schaefer (USA) [23] 3 93 4
Gammal (Egypt) [28] 35 25 40
Hiddlestone (N Zealand) [31] 39 35 27
Williams (UK) [30] 42 34 24
Williamson (USA) [27] 20 36 54
Fein (USA) [29] 10 67 23
AVERAGE 36 41 23
Data from Gluck JC, Gluck PA. The effects of pregnancy on asthma: a prospective study. Ann
Allergy 1976;37:165.
68 gluck & gluck
their diagnosis probably was correct. The course of asthma during pregnancy
was assessed through changes in their medications. Asthma was said to be worse
if medication use increased, and was considered improved if medication use
decreased. Over time, asthma treatment has changed. In the past, medications
would not have included inhaled steroids, which are a mainstay of treatment today.
Thus, evaluation of older studies may not be comparable to evaluation of more
recent series.
Other retrospective studies included patients from obstetric clinics [23] or
general clinics [26]. These women generally were not comanaged with an asthma
specialist. Some of these patients could have been misdiagnosed. In addition, the
use of appropriate asthma medication was less likely.
The severity of asthma before or after pregnancy was not noted in any of these
studies. Pulmonary function testing as an objective measure was not always avail-
able, so the physician’s and patient’s clinical assessments were relied on to evaluate
changes in the course of asthma. The course of asthma during pregnancy as deter-
mined from these early studies definitely is variable. Local environmental conditions
probably are not a factor because there were similar data from different locations.
Prospective studies
Since 1976, several studies have evaluated the course of asthma during
pregnancy prospectively. The latest edition of Williams Obstetrics advised
that the ‘‘treatment of acute asthma during prenancy is similar to that for the
nonpregnant asthmatic’’ [47]. In pregnant patients, undertreatment of asthma,
owing to fears of adverse effects on the fetus, continued to be a major problem,
especially among obstetricians. Most patients in these prospective studies were
enrolled from maternity clinics and were followed through delivery and into post
partum [4,6,18,32,33]. One study enrolled patients from an asthma clinic before
pregnancy and used nonpregnant female controls [34]. The criterion for entry into
the studies was a history of asthma. Three studies included a control cohort of
pregnant, nonasthmatic women, which is more helpful in assessing the effect of
asthma on pregnancy. Patients reported their prepregnant condition, and many
were followed post partum, which served as another control. Again, when the
Table 3
Effect of pregnancy on asthma: prospective studies
Study n Improved (%) Same (%) Worse (%)
Gluck [6] 47 14 43 43
Schatz [18] 330 28 33 35
Stenius-Aarniala [32] 198 18 40 42
White [33] 31 69 22 9
Juniper [34] 16 50 37.5 12.5
Schatz [4] 1624 23 47 30
AVERAGE 2246 33.6 37 28.5
total population of asthmatics in these studies is considered, about one third were
improved, one third were unchanged, and one third were worse (Table 3).
Six prospective studies followed the course of asthma through pregnancy. Of
those, five stratified their subjects according to the severity of asthma at the
beginning of pregnancy [4,6,32–34]. Gluck and Gluck [6] followed all patients
who had a history of asthma from their first visit to a prenatal clinic. Patients were
stratified by severity of asthma based on frequency of symptoms before preg-
nancy. Severe asthmatics (12 patients) had symptoms at least weekly. Moderate
asthmatics (10 patients) had attacks at least monthly, but not as frequently as the
severe group. Those who had symptoms less often than monthly, but with a
history of one or more attacks within the preceding 5 years, were considered mild
asthmatics (25 patients).
In contrast, Stenius-Aarniala and colleagues [32] divided their patients by
severity based on medication requirements and clinical course during pregnancy
(Table 4). White and colleagues [33] stratified a group of 31 patients at the time
of entry based on medication usage. Mild asthmatics required only occasional
bronchodilators, moderate asthmatics used bronchodilators more than half of the
days or required inhaled steroids, and severe asthmatics required oral steroids.
Only one was considered to have severe disease, and more than half (17/31) had
mild disease.
Juniper and colleagues [34] divided their patients based on medications that
were required to control asthma symptoms. They used statistical analysis that was
based on the class of drug and dosage, and methacholine challenge. There were
5 mild asthmatic patients, 1 moderate asthmatic patient, and 10 severe asthmatic
patients in this study. The clinical course of asthma during pregnancy was as-
sessed for the group overall. Eight patients improved, 6 were unchanged, and
2 deteriorated. In addition, using the methacholine challenge, they documented
objective changes during pregnancy.
Schatz and colleagues [4] evaluated pregnant patients at less than 25 weeks’
gestation who reported asthma symptoms in the previous 6 months. Frequency
of asthma symptoms in the past month, forced expiratory volume in 1 second
(FEV1), and daily medications were assessed on entry into the study. The patients
were divided into mild (873), moderate (814), and severe (52) categories. When
Table 4
Classification of asthma severity during pregnancy
Group (n) Medication Exacerbation Hospitalization
Very mild (56) None or inhaled bronchodilators, sodium None None
cromoglycate or beclomethasone
Mild (52) As above plus oral bronchodilator None None
Moderately severe (56) As above One or more None
Severe (34) As above One or more One or more
Data from Stenius-Aarniala B, Piirila P, Teramok K. Asthma and pregnancy: a prospective study
of 198 pregnancies. Thorax 1988;43:13.
70 gluck & gluck
assessing the change in asthma during pregnancy overall, 23% improved, 47%
were unchanged, and 30% were worse.
Because the course of asthma during pregnancy is related to the severity of
asthma (see later discussion), variations in findings among studies can be at-
tributed, at least in part, to the different proportions of the asthma severity sub-
groups. In the two studies that had a similar severity distribution [6,32], the
results regarding asthma course were similar.
Severity
When the course of asthma was evaluated in patients who had mild asthma
with occasional wheezing and bronchodilator usage, most showed no change
in their disease. Gluck and Gluck [6] found that 72% of mild asthmatics
were unchanged during pregnancy, 16% worsened, and 12% improved. Stenius-
Aarniala and colleagues [32] found that 22% of mild asthmatics were worse
during pregnancy and improved after delivery. Schatz and colleagues [4] classified
patients as having mild asthma if they had fewer than 8 days of symptoms in the
4 weeks before enrollment, no daily medications, and an FEV1 of 80% or greater.
Of these 873 patients, 28% were worse during their pregnancy, whereas the others’
disease remained mild. The patients in White and colleagues’ study [33] were mild
or moderately severe at the start of pregnancy; most of these patients improved or
had no change in severity. Improvement was noted especially in the third trimester
in peak flow measurements and the perception of asthma symptoms. Thus, it
seems that patients who have mild asthma before pregnancy usually do not
experience exacerbation of the disease during pregnancy.
When severe asthmatics were evaluated, a different picture emerged. Gluck
and Gluck [6] found that none of their severe asthmatics improved during preg-
nancy, 17% were unchanged, and 83% were worse, with nine hospitalizations
for status asthmaticus in 12 patients. In the larger study by Stenius-Aarniala
Table 5
Asthma morbidity during pregnancy after enrollment in the study in relationship to initial asthma
severity classification
Asthma Hospitalized Unscheduled Oral corticosteroid Asthma symptoms
severity for asthma visita for asthma Exacerbationb during labor/delivery
Mild 20 (2.3%) 99 (11.3%) 19 (2.2%) 110 (12.6%) 116 (13.3%)
(n = 873)
Moderate 55 (6.8%), 157 (19.3%), 71 (8.7%), 209 (25.7%), 171 (21.0%),
(n = 814) P b.0001c P b.0001 P b.0001 P b.0001 P b.0001
Severe 14 (26.9%), 19 (36.5%), 20 (38.5%), 27 (51.9%), 24 (46.2%),
(n = 52) P b.0001 P = .003 P b.0001 P b.0001 P b.0001
a
Includes unscheduled antenatal, primary care or emergency department visit for asthma.
b
Hospitalization, unscheduled visit, or oral corticosteroid course for asthma.
c
P values indicate comparison to group directly above.
From Schatz M, Dombrowski MP, Wise R, et al. Asthma morbidity during pregnancy can be predicted
by severity classification. J Allergy Clin Immunol 2003;112:285; with permission.
and colleagues [32], the most severe asthmatics had significantly lower FEV1
and maximum flow at 50% vital capacity measurements during the last month of
pregnancy. When surveyed post partum, 34.5% of all patients believed that their
asthma was better than during pregnancy. Most of the patients who had severe
asthma (56%) felt better after delivery. A large multicenter study of women who
had moderate asthma (defined as 8 or more days of symptoms in the previous
4 weeks, daily medication [not oral steroids], and an FEV1 of 60%–80% of
predicted) found that they had more symptoms than did mild asthmatics, and less
symptoms than did severe asthmatics during pregnancy (Table 5) [4]. Patients
who had severe asthma, defined as an FEV1 of less than 60% of predicted or who
took daily oral steroids, had the most asthma morbidity of all patients studied
(Table 6). Grouping moderate and severe asthmatics together, 77% were un-
changed and 23% had milder symptoms in pregnancy [4]. These studies show
that the course of asthma in pregnancy varies with the severity of asthma before
pregnancy, regardless of previous treatment. Women who have more severe
asthma tend to have exacerbations of their disease with more symptoms and
medications required than in women who have milder disease.
Stage of pregnancy
All stages of pregnancy are not the same for patients who have asthma. The
first trimester generally is tolerated well in asthmatics who have only rare
exacerbations [6,18,33,34]. Gluck and Gluck [6] found that increased symptoms
did not occur before the fourth month of gestation, and the peak incidence of
flares occurred during the sixth month, regardless of the severity of the asthma.
Table 6
Asthma morbidity for the entire pregnancy in relationship to the change in initial versus final asthma
severity classification
Asthma
symptoms
Initial/final Hospitalized Unscheduled Oral steroid Asthma during labor/
asthma severity for asthma visita for asthma exacerbationb delivery
Mild/mild (n = 565) 11 (2.0%) 75 (13.3%) 3 (0.5%) 80 (14.2%) 60 (10.6%)
Mild moderate or 21 (8.5%), 83 (33.7%), 20 (8.1%), 92 (37.4%), 45 (18.3%),
severe (n = 246) P b.0001c P b.0001 P b.0001 P b.0001 P = .0028
Moderate or 107 (17.1%) 264 (42.1%) 110 (17.5%) 310 (49.4%) 155 (24.7%)
severe/moderate
or severe (n = 627)
Moderate or severe/ 9 (4.8%), 50 (26.9%), 3 (1.6%), 57 (30.7%), 31 (16.8%),
mild (n = 186) P b.0001 P = .0002 P b.0001 P b.0001 P = .0216
Includes only patients with more than 30 days of follow-up data.
a
Includes unscheduled antenatal, primary care, or emergency department visit for asthma symptoms.
b
Hospitalization, unscheduled visit, or oral corticosteroid course for asthma.
c
P values indicate comparison to group directly above.
From Schatz M, Dombrowski MP, Wise R, et al. Asthma morbidity during pregnancy can be predicted
by severity classification. J Allergy Clin Immunol 2003;112:286; with permission.
72 gluck & gluck
Schatz and colleagues [18] found an increase in symptoms between 29 and

36 weeks’ gestation in women whose asthma was worse during pregnancy.
Juniper and colleagues [34] also found an increase in symptoms in the second
and third trimesters compared with preconception in 5 of 16 patients. Using
methacholine challenge, objective changes were documented during pregnancy
that showed improvement in the second trimester in the group as a whole [34].
Stenius-Aarniala and colleagues [35] found that most acute exacerbation occurred
between 17 and 24 weeks of pregnancy.
In the last month of pregnancy, asthma improves in many mild–moderate
asthmatics [18,33]. Stenius-Aarniala and colleagues [32] found lower FEV1
measurements in the last month of pregnancy in patients who had severe asthma,
but patients were less likely to have exacerbations at this time. Schatz and
colleagues [18] assessed asthma symptoms at 4-week intervals throughout preg-
nancy; fewer and less severe symptoms were found in the last 4 weeks of preg-
nancy than during any other interval (Fig. 1). Even among women whose asthma
worsened during pregnancy, there was relative improvement in the last 4 weeks
(Fig. 2) [18]. These studies suggest that the first trimester and the last month of
pregnancy are mostly free of asthma exacerbations, and that the second and earlier
part of the third trimesters have more potential for increased asthma symptoms.
In labor and delivery
Approximately 10% to 20% of asthmatics have asthma symptoms during la-

bor and delivery [4,18]. These symptoms usually are mild and can be controlled
Fig. 1. Mean number of symptomatic days (total days of wheezing [A], days of sleep interference [B],
days of interference with normal activity [C]) versus 4-week gestational intervals in 75 women
(P values for significant differences noted). (From Schatz M, Harden K, Forsythe A, et al. The course
of asthma during pregnancy, post partum, and with successive pregnancies: a prospective analysis.
J Allergy Clin Immunol 1988;81:511; with permission.)
easily [32]. In one study of 360 patients, 37 patients were symptomatic during
labor and delivery. Of these, 54% required no treatment, 41% used inhaled
bronchodilators, and 5% were given intravenous aminophylline [18]. The inci-
dence of asthma symptoms during labor and delivery increases with increased
asthma severity, and there are significant differences between patients who
have mild (12.3%), moderate (22.4%) and severe (44.4%) disease [4]. Mabie and
Fig. 2. Mean number of symptomatic days versus 4-week gestational intervals in each of 25 women
whose asthma got worse (dot–dash line), got better (dashed line), or stayed the same (solid line)
during pregnancy (P values for significant differences are noted) (A) Total days of wheezing.
(B) Days of interference with sleep caused by asthma. (C) Days of interference with normal activity
caused by asthma. (From Schatz M, Harden K, Forsythe A, et al. The course of asthma during
pregnancy, post partum, and with successive pregnancies: a prospective analysis. J Allergy Clin
Immunol 1988;81:512; with permission.)
74 gluck & gluck
Fig. 2 (continued).
colleagues [36] reported an 18-fold increased risk for asthma exacerbation during
delivery by cesarean section compared with vaginal delivery.
Course of asthma post partum
In general, after delivery, asthma returns to the severity that was present before
pregnancy. If the course of asthma during pregnancy was unchanged, the disease
remained the same after delivery in 72% of the women studied. When asthma
changed during pregnancy, it returned to the prepregnancy state within 3 months
in 74% of women (Fig. 3) [18]. Similarly, 56% of women who had severe asthma
during pregnancy had fewer symptoms after delivery, whereas only 22% of mild
asthmatics improved after giving birth [32]. These data support the concept that
the changes in the course of asthma during pregnancy are more than just random
fluctuations in its natural course. Several other studies observed that asthma
changes that occurred during pregnancy disappeared within 3 months after de-
livery [6,24,25,33,34].
Course of asthma during subsequent pregnancies
Several studies found that the course of asthma in individual women is simi-
lar during subsequent pregnancies. Gammal and Warraki [28] reported consis-
tency in deterioration in 29 of 33 patients and consistent improvement in 23 of
28 patients. Williams [30] found that 63% of his patients had similar courses; all
of Jensen’s [24] patients had consistent courses of asthma during subsequent
pregnancies. Stenius-Aarniala and colleagues [32] followed 13 women through
two pregnancies, but adjusted medications at an earlier stage in the second
pregnancy, which led to better asthma control. Schatz and colleagues [18] noted
Fig. 3. Mean number of symptomatic days versus 4-week intervals from 17 weeks of pregnancy to
12 weeks post partum in each of 25 women whose asthma got worse (solid line), got better (hatched
line) or stayed the same (dashed line) during pregnancy. (A) Total days of wheezing. (B) Days
of sleep interference caused by asthma. (C) Days of interference with normal activity caused by
asthma. (From Schatz M, Harden K, Forsythe A, et al. The course of asthma during pregnancy,
post partum, and with successive pregnancies: a prospective analysis. J Allergy Clin Immunol 1988;
81:513; with permission.)
76 gluck & gluck
Fig. 3 (continued).
exact concordance in the course of asthma in 58.8% of 34 women who were seen
through two pregnancies.
Other factors that affect asthma during pregnancy
Reluctance to treat
Asthma severity and control of asthma are important risk factors during preg-
nancy. Factors, such as reluctance to treat, result in poor control of asthma during
pregnancy. Additionally, decreased compliance may occur because of a patient’s
concerns about the safety of medication for the fetus.
A study of treatment of acute asthma in emergency departments across the
United States included 551 women (51 pregnant and 500 not pregnant) [37]. Both
groups had similar durations of symptoms and peak expiratory flow rates (51%);
however, there was a significant difference in treatment. Pregnant women were
less likely to be given systemic corticosteroids (44% versus 66%) in the emer-
gency department. This decrease cannot be attributed solely to concern about
steroid exposure in the first trimester because the proportion of women who
received corticosteroids was similar in all trimesters: 53% first trimester, 40%
second trimester, and 50% third trimester. Among those patients who were
admitted, pregnant women had significantly lower final peak expiratory flow rate
measurements in the emergency department, and had significantly longer hospi-
tal stays. On discharge from the emergency department, pregnant patients
were significantly less likely to be given systemic corticosteroids (P =.002). This
undertreatment may explain, in part, the continued asthma symptoms at 2-week
follow-up in pregnant patients (three times more common than in nonpregnant

patients; P = .02.) Only 41% of pregnant asthmatic women who were seen in
the emergency departments were on inhaled corticosteroids when they pre-
sented with exacerbations, which is another indication of the undertreatment of
asthma in pregnancy [37].
Atopy and allergens
Atopy can contribute to allergic symptoms and asthma when there is seasonal
or environmental exposure to specific allergens. Serum IgE or skin prick tests
have been used to measure atopy in pregnancy and its effect on asthma [6,32].
Most asthmatic women were atopic in these studies. Stenius-Aarniala and col-
leagues [32] found that the atopic women had milder asthma, and had signifi-
cantly fewer hospital admissions than in the nonatopic women. Of the women
whose serum IgE increased during their pregnancies, Gluck and Gluck [6] found
that asthma remained the same or worsened. In a group of inner city women,
Henderson and colleagues [38] found that worsening asthma during pregnancy
was associated with increased levels of cockroach-specific IgE. Interactions be-
tween pregnancy, atopy, and environmental exposures have not been charac-
terized otherwise in pregnant asthmatic women.
Respiratory tract infections
A decrease in cell-mediated immunity may make the pregnant patient more

susceptible to viral infections [39,40]. It was reported that viral infections are
the most common precipitators of severe asthma during pregnancy [31]. In ad-
dition, sinusitis may exacerbate asthma, and sinusitis was reported to be six times
more common in pregnant women compared with nonpregnant women [41].
Pneumonia is found more often in asthmatic women, compared with non-
asthmatic women, during pregnancy. Of more than 27,500 pregnant women,
60 had pneumonia during pregnancy [42]. A history of asthma was reported
by 37% of this group, compared with 5% in the control group of women who
did not have pneumonia and who delivered at the same time. Those who had
asthma had a greater than fivefold increased risk for developing pneumonia
during pregnancy. These women were more likely to be treated for preterm labor,
and delivered at an earlier gestational age [42]. Other studies also found an
increased history of asthma (8%–25%) in pregnancies that were complicated by
pneumonia [43,44].
Smoking
Smoking is a significant risk factor for adverse pregnancy outcomes, and

exacerbates asthma. A survey of new mothers in Australia showed that 21% had
a history of asthma and 12% had active asthma. Overall, 22.7% of the women
smoked during pregnancy. Current asthmatics were more likely to smoke than
78 gluck & gluck
Table 7
Asthma-related health care use by racial group among pregnant asthmatics
Health care outcome Whites (3030) Blacks (1285) Adjusted rate ratioa (W/B)
ED visit (11%) 8.7% 16.7% 1:1.89
Rescue CS (12.7%) 11.9% 14.6% 1:1.35
Hospitalized (6.3%) 5.2% 9% 1:1.73
Abbreviations: CS, corticosteroids; ED, emergency department; W/B, white/black.
a
Adjusted for age, education, smoking, high-risk (all P b.05).
Data from Carroll KN, Griffin MR, Gebretsadik T, et al. Racial differences in asthma morbidity during
pregnancy. Obstet Gynecol 2005;106:69.
were nonasthmatics, although this difference was not statistically significant [45].
A review of the data that were collected prospectively from 568 asthmatics
did not show an association between smoking and worsening of asthma during
pregnancy [13]. This might explain why more asthmatics did not stop smoking
during their pregnancies.
Race
A recent study followed 4315 low-income asthmatic women from at least

6 months before pregnancy and through pregnancy. There were 3030 white pa-
tients and 1285 black patients; an average of 11% visited the emergency depart-
ment during pregnancy and 6.3% were hospitalized. Black women were more
likely to be treated with corticosteroids (14.6% versus 9% for whites), although
their incidence of smoking was much lower than whites (15% versus 50%). After
adjusting for age, education, smoking, and high-risk pregnancies, the asthma-
specific morbidity in pregnancy was significantly higher in blacks (Table 7) [46].
Summary
The course of asthma is changed by pregnancy in variable ways for unknown

reasons. Although the prospective studies used different criteria to stratify the
severity of the patients’ asthma, their conclusions were remarkably similar. Over-
all, an equal number of women have asthma symptoms that improve, worsen, or
are unchanged through pregnancy. Asthma symptoms can worsen during preg-
nancy because of identifiable factors, such as infection, gastroesophageal re-
flux disease, reduction of appropriate medications by physician or patient, and
smoking. Undertreatment, which remains a problem during pregnancy, can lead
to continued difficulty with asthma.
Severe asthmatics tend to have increased symptoms compared with mild
asthmatics. If symptoms worsen, it usually occurs in the second and third tri-
mesters, with the peak in the sixth month. Generally, there is improvement in
asthma in the last 4 weeks of pregnancy.
During labor and delivery, only 10% to 20% of asthmatics have symptoms;
severe asthmatics are more likely to have exacerbations. Asthma tends to return
to the prepregnancy state within 3 months post partum. Successive pregnancies
tend to have a similar course in each individual.
Every asthmatic woman should be maintained on appropriate medications
and followed carefully throughout pregnancy, especially in the second and third
trimesters. Asthma specialists should be available for collaborative care when
asthma is uncontrolled, or if there is an exacerbation. A timely adjustment in
treatment for any changes in asthma course that might occur ensures the best
control of the disease in the face of complex multiple influences.
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26 (2006) 81 – 92
Outcomes of Pregnancy in Asthmatic Women

Mitchell P. Dombrowski, MD
Department of Obstetrics and Gynecology, St. John Hospital, 22151 Moross Road,
Suite 313, Detroit MI 48236, USA
Asthma probably is the most common potentially serious medical complica-

tion of pregnancy. This article reviews the literature on the maternal and perinatal
effects of asthma during pregnancy. Adverse effects of asthma may be, in part, a
function of asthma therapy, especially in the case of long-term oral corticosteroid
administration. The effects of asthma medications during pregnancy are discussed
elsewhere in this issue.
Existing studies on the effects of asthma on pregnancy outcomes have had
inconsistent results in regard to perinatal mortality, prematurity, low birth weight,
neonatal hypoxia, cesarean delivery, hemorrhage, preeclampsia, and other com-
plications. Until recently, there have been few large, prospective studies of
asthma during pregnancy. Many of the older studies have several methodologic
inadequacies, including low power; lacking or inadequate control for confound-
ers; little information regarding asthma severity, management, or control; and
time frames that do not reflect current management.
Studies before 1990
In 1961, Schaefer and Silverman [1] published their study of 293 patients who
had asthma who were managed from 1953 to 1959. This descriptive study did
not use any statistics, but they found a slightly higher incidence of spontaneous
abortion (11.0% versus 9.4%) and low birth weight (8.9% versus 6.2%) among
E-mail address: mitchell.dombrowski@stjohn.org
82 dombrowski
the cohort that had asthma. In 1970, Gordon and colleagues [2] compared out-
comes for 265 births among women who had asthma with 30,861 controls. They
found no significant increase in prematurity, but the perinatal mortality rate among
asthmatics (5.9%) was increased significantly compared with controls (3.2%).
Bahna and Bjerkedal [3] used the Medical Birth Registry of Norway to
examine pregnancy outcomes for births during 1967 and 1968. Their 1972 study
had 381 women who had asthma and 112,530 control subjects. The cohort with
asthma had significantly more hyperemesis gravidarum (2.1% versus 0.8%),
hemorrhage (4.7% versus 2.2%), preeclampsia (10.5% versus 4.7%), preterm
birth (7.4% versus 5.0%), hypoxia at birth (1.6% versus 0.7%), and low birth
weight (7.1% versus 3.7%) compared with controls. There were no significant
differences for malformations, birth injury, or perinatal mortality rates.
In 1986, Dombrowski and colleagues [4] published a study that was designed
to evaluate the effects of theophylline on the incidence of preeclampsia. They
reported 153 pregnancies among women who had asthma compared with
116 controls born from 1982 to 1985. There were no differences in gestational
age at birth or birth weight. The frequency of preeclampsia was decreased
significantly among the cohort that was treated with theophylline.
A Finnish prospective study in 1988 by Stenius-Aarniala and Teramo [5]
reported results for 198 births from 1978 to 1982 among asthmatics and 198 con-
trols who were matched for age and parity. Asthma was classified as very mild,
mild, moderately severe, and severe. The incidence of preeclampsia was sig-
nificantly higher among those who had severe asthma (29%) compared with
those who had very mild asthma (9%). It also was significantly more common
among those who received systemic steroids (25%) than among those who did
not (10%). Cesarean sections were increased significantly among women who
had asthma (28% versus 17%). There were no differences in regards to
gestational age at delivery, birth weight, perinatal death, low Apgar score,
respiratory difficulty, and malformations.
Studies from 1990 through 1999
In 1990, Lao and Huengsburg [6] reported a retrospective study of 87 gravidas

who had asthma and 87 controls who delivered in Hong Kong from 1984 to
1987. They reported an increased incidence of birth weight of less than 2500 g
(10.3% versus 1.1%) and cesarean delivery (25.3% versus 9.2%) among
asthmatics. There were no significant differences in gestational age at delivery,
mean birth weight, postpartum hemorrhage, or perinatal complications.
Starting in 1990, the Schatz group began the first of many contributions to
the literature on asthma in pregnancy [7]. This was a prospective study of
360 pregnancies from 1978 to 1984. Spirometry was performed; a small (r = 0.11),
but significant, direct correlation was demonstrated between birth weight and
individual mean percent predicted forced expiratory volume in 1 second (FEV1)
outcomes of pregnancy in asthmatic women 83
during pregnancy. No significant relationships were observed between lower

FEV1 and the incidences of preterm birth or preeclampsia. By regression analysis,
smoking (odds ratio [OR], 3.2) and lower FEV1 (OR, 3.0) were associated in-
dependently with birth weights in the lower quartile.
In 1992 Mabie and colleagues [8] published a retrospective study of 200 women
who delivered between 1986 and 1989. The frequency of cesarean section was
increased significantly among women who had moderate or severe asthma
compared with those who had mild asthma (75% versus 33%). The frequency of
intrauterine growth retardation (IUGR) was increased significantly among the
cohort that moderate and severe asthma (16%) compared with women who
had mild asthma (4%), but there was no differences in the rates of preterm de-
livery or preeclampsia.
In 1992, Perlow and colleagues [9] retrospectively identified 81 asthmatics
and 130 control subjects from 1985 to 1990. Of the gravidas who had asthma,
31 were considered to be steroid dependent. Gestational diabetes (OR, 19.1; 95%
confidence interval [CI], 1.9–138.1) and primary cesarean section (OR, 2.6; 95%
CI, 1.1–6.6) were increased among the steroid-dependent group compared with
controls. Preeclampsia and IUGR were not increased significantly. Compared
with controls, the frequency of delivery at less than 37 weeks’ gestation was
increased among the group that was not steroid dependent (OR, 4.0; 95%
CI, 1.1–15.5) and was increased markedly among the steroid-dependent group
(OR, 29.9; 95% CI, 8.6–111.3). These investigators were the first group to report
the effects of asthma on severe prematurity; compared with controls, there was a
fourfold, nonsignificant increase of delivery at less than 32 weeks’ gestation for
gravidas who had asthma.
Lehrer and colleagues [10] used a computerized database of 21,115 women
who delivered from 1987 to 1991. Of these, 136 had asthma during pregnancy.
Pregnancy-induced hypertension was increased (OR, 2.52; 95% CI, 1.47–4.35)
among the asthma cohort when logistic regression methods controlled for the
confounding effects of ethnicity, age, parity, and prepregnancy weight. Doucette
and Bracken [11] conducted a prospective cohort study of 3891 women who
delivered a singleton birth from 1980 to 1982, of whom 31 has asthma. They
found no association of asthma with birth weight, and reported a nonsignificant
trend for preterm delivery.
In a prospective study, Jana and colleagues [12] reported their experience in
India for 182 asthmatics and 364 controls that delivered from 1983 to 1992.
There were no significant differences in regards to mode of delivery, prematurity
rate, low birth weight, or perinatal mortality. There was a significant decrease in
birth weight (2469 F 571 g versus 2842 F 494 g) among the 15 gravidas who
had uncontrolled, severe asthma who required hospitalization.
In 1995, Schatz and colleagues [13] published a prospective, controlled incep-
tion cohort study of 486 asthmatics and 486 matched controls from 1978 to 1989.
This study was important because it was large, prospective, and used spirometry
and active management of patients who had asthma. Asthma was not associated
significantly with increased preeclampsia, perinatal mortality, preterm birth, low
84 dombrowski
birth weight, IUGR, or congenital malformations. The investigators suggested

that the perinatal outcomes for women who had actively managed asthma are
comparable to those for the nonasthmatic population.
In 1996, Stenius-Aarniala and colleagues [14] reported outcomes for 504 preg-
nant women who had asthma that was managed by pulmonary specialists and
237 healthy parturients from 1982 to 1992 in Finland. There were no significant
differences for length of gestation, postpartum hemorrhage, low birth weight, or
nonelective cesarean section. Forty-seven women who had asthma had an acute
attack during pregnancy; the frequency of exacerbations increased during preg-
nancy until 21 to 24 weeks’ gestation, and then declined until 40 weeks’ ges-
tation. Women who used inhaled corticosteroids had a significant reduction in the
risk of having an exacerbation (relative risk [RR], 0.22; 95% CI, 0.11–0.44).
In a 1998 publication, Minerbi-Codish and colleagues [15] reported their
prospective study that was conducted during 1993 and 1994. Forty-nine patients
had mild asthma, 36 had moderate asthma, and 16 had severe asthma; there were
77 control subjects. According to multivariate analyses, there were no significant
associations of asthma to birth weight of less than 2500 g, preterm delivery, small
for gestational age neonates (SGAs), or cesarean section rate. Asthmatic women
were significantly more likely to suffer from respiratory and urinary tract infec-
tions (RR, 10.6).
A 1998 retrospective cohort study by Alexander and colleagues [16] was con-
ducted in Canada between 1991 and 1993. This cohort included 3709 controls;
375 asthmatics who took no medication; 303 asthmatics who took b-agonists
only; and 139 asthmatics who took ‘‘steroids,’’ which presumably included in-
haled and systemic corticosteroids. No statistical differences were found for any
asthma group regarding preterm birth, gestational diabetes, low birth weight,
respiratory distress syndrome, congenital anomalies, or cesarean section rate.
Neonatal jaundice was increased among the group that was treated with steroids
(OR, 1.9; 95% CI, 1.1–3.4). Antepartum hemorrhage was increased (OR, 2.2;
95% CI, 1.3–3.7) among the cohort that received steroids, and postpartum
hemorrhage was increased (OR, 1.9; 95% CI, 1.3–2.7) among asthmatic women
who took no medication, after controlling for confounders by means of logistic
regression analysis.
In contrast, another study that was published in 1998 found multiple adverse
maternal and perinatal associations. Demissie and colleagues [17] reported a large
analysis of singleton live deliveries in New Jersey hospitals between 1989 and
1992 using International Classification of Diseases, Ninth Revision, Clinical Modi-
fication (ICD-9-CM) codes linked with birth certificates. A total of 2289 had
a code for asthma, and 9156 controls were selected randomly. After control-
ling for the effects of confounding variables, maternal asthma was associated
significantly with preterm delivery (OR, 1.36; 95% CI, 1.18–1.55), SGAs (OR,
1.26; 95% CI, 1.10–1.45), congenital anomalies (OR, 1.37; 95% CI, 1.12–1.68),
and increased neonatal length of stay (OR, 1.44; 95% CI, 1.25–1.65). Adverse
maternal outcomes included preeclampsia (OR, 2.18; 95% CI, 1.68–2.83), placenta
previa (OR, 1.71; 95% CI, 1.05–2.79), cesarean delivery (OR, 1.62; 95% CI, 1.46–
1.80), and increased length of stay (OR, 1.86; 95% CI, 1.6–2.15). No information
was available regarding asthma severity or management.
Studies since 2000
Wen and colleagues [18] used the Canadian Institute for Health Information
and ICD-9-CM codes to identify women who had asthma and controls from 1989
to 1996. Eight thousand six hundred and seventy-two gravidas who had asthma
were compared with 34,688 controls. Logistic regression analysis was used to
control for potential confounding factors. Asthma was found to be associated
with multiple adverse pregnancy outcomes: preterm labor (OR, 1.78; 95%
CI, 1.53–2.07), preeclampsia (OR, 1.84; 95% CI, 1.64–2.05), gestational diabetes
(OR, 2.26; 95% CI, 2.02–2.53), placenta previa (OR, 1.50; 95% CI, 1.11–2.04),
abruptio placenta (OR, 1.63; 95% CI, 1.35–1.96), cesarean delivery (OR, 1.48;
95% CI, 1.40–1.57), and postpartum hemorrhage (OR, 1.51; 95% CI, 1.36–1.68).
There was no significant increase in fetal deaths.
Kallen and colleagues [19] used the Swedish Medical Birth Registry and the
Hospital Discharge Register to collect data for births between 1984 and 1995.
This study used multiple criteria for identifying subjects who had asthma. In the
total asthma cohort (n = 36,985), they found an increased incidence of pre-
eclampsia (OR, 1.15; 95% CI, 1.08–1.23), maternal diabetes (OR, 1.34; 95% CI,
1.17–1.54), preterm birth at less than 37 weeks’ gestation (OR, 1.15; 95% CI,
1.09–1.21), low birth weight of less than 2500 g (OR, 1.21; 95% CI, 1.14–
1.29), and postterm birth at greater than 41 weeks’ gestation (OR, 1.25; 95% CI,
1.19–1.31), but not congenital malformations (OR, 1.05; 95% CI, 0.99–1.10.
The ORs were all higher for these outcomes in the 1396 asthmatic mothers who
were identified in the hospital discharge registry and the antenatal records, which
were believed to represent ‘‘the most certain and severe cases of asthma during
pregnancy.’’ No information was presented regarding asthma management in
these patients..
Liu and colleagues [20] used ICD-9-CM codes and a comprehensive admin-
istrative database to identify 2193 gravidas who had asthma and 8772 controls in
Quebec, Canada from 1991 to 1996. After adjusting for potential confounders,
asthma was associated with increased preterm births (OR, 1.40; 95%
CI, 1.18–1.66), very small for gestation age (OR, 1.9; 95% CI, 1.47–2.44), large
for gestational age (OR, 1.17; 95% CI, 1.01–1.35), preeclampsia (OR, 1.77; 95%
CI, 1.33–2.35), and chorioamnionitis (OR, 2.75; 95% CI, 2.31–3.27). There
were no significant associations for congenital anomalies, antepartum hemor-
rhage, or postpartum hemorrhage.
In 2001, Olesen and colleagues [21] used the Birth Registry data from Den-
mark for 303 asthmatics who gave birth between 1991 and 1996. Compared
with controls, there were no significant differences for gestational age or birth
weight. Among the 78 women who decreased asthma medications during preg-
nancy, birth weight decreased significantly by 116.9 g (95% CI, 15.9–217.8).
86 dombrowski
Data on pregnancy outcomes were gathered (1997–1999) during the recruit-

ment phase of the Childhood Asthma Prevention Study by Mihrshahi and col-
leagues [22]. There were 340 pregnancies of asthmatic mothers and 269 controls.
Hypertension was more common among asthmatics. There were no significant
differences for gestational diabetes, labor or delivery complications, or adverse
perinatal outcomes.
Norjavaara and de Verdier [23] reported data from the Swedish Medical Birth
Register for 1995 to 1998. This study was limited to the 2968 mothers who
reported using inhaled budesonide during pregnancy; therefore, it is not appli-
cable for answering questions about general asthma outcomes during pregnancy.
Because the subjects in this study required an inhaled corticosteroid, they
presumably had persistent asthma. Therefore, if more severe asthma increases the
likelihood of pregnancy complications, the pregnancy outcomes in this study
would be expected to be worse than studies that also enrolled subjects who had
mild intermittent asthma. Nonetheless, there were no clinically significant dif-
ferences in birth weight, gestational age, or stillbirths in these patients compared
with all pregnancies in the Swedish Medical Birth Register for those years.
The risk of preterm delivery was examined by Sorensen and colleagues [24] in
a nested case control study of women who participated in screening protocol for
neural tube defects and Down’s syndrome during 1994 and 1995. Four hundred
and twenty-four controls were compared with 312 women who had delivered
early. Significantly more subjects had asthma (n = 20) in the cohort who gave
birth early compared with controls (n = 14) (OR, 2.37; 95% CI, 1.15–4.88) after
adjusting for age, ethnicity, parity, Medicaid payment status, and smoking.
In a 2003 prospective study, Murphy and colleagues [25] reported outcomes
for 138 pregnancies that were complicated by asthma compared with 44 con-
trols. Among gravidas who were not treated with inhaled corticosteroids, female
newborn birth weights (3094 F 120 g) were reduced significantly (P = .027)
compared with controls (3528 F 86 g) and those who were treated with inhaled
corticosteroids (3375 F 90 g). In contrast, gravidas who were not treated with
inhaled corticosteroids had larger male neonates (3701 F 89 g) compared with
controls (3602 F 166 g) and those who were treated with inhaled corticosteroids
(3446 F 88 g; P = .192).
Two recent, large, multicenter, prospective cohort studies have evaluated the
effects of maternal asthma on perinatal outcomes [26,27]. These studies were
unique in that they contained information regarding asthma severity and man-
agement. In 2003, Bracken and colleagues [26] reported on 1333 women who
had no history of asthma, and 873 pregnant women who had asthma. Ap-
proximately half of the study population was classified as having intermittent
asthma (no asthma symptoms or treatment during pregnancy). Preterm delivery
was not associated with asthma diagnosis or severity; however, oral corticosteroid
use was associated with a reduction in gestation of 2.22 weeks (P = .001), and
theophylline use was associated with a reduction of 1.11 weeks (P = .002). The
diagnosis of asthma was not associated with a significant increase in SGAs.
Increasing asthma severity and symptoms were associated with SGAs; those who
had daily symptoms (OR, 2.25; 95% CI, 1.25–4.06) and those who had moder-
ate, persistent asthma (OR, 2.01; 95% CI, 1.11–3.65) manifested increased risks.
No specific medication type was observed to lead to an increased risk of fetal
growth restriction. In a related publication, Triche and colleagues [28] reported
that asthma was not associated with an increased incidence of preeclampsia;
however, preeclampsia was increased significantly among the cohort who had
daily asthma symptoms (OR, 3.36; 95% CI, 1.24–9.14) and among those who
received theophylline (OR, 1.16; 95% CI, 1.02–1.33). These data suggest that
poor asthma control—by causing acute or chronic maternal hypoxia—may be the
most remedial responsible factor, and support the important generalization that
adequate asthma control during pregnancy is important in improving maternal–
fetal outcome.
The National Institute of Child Health and Human Development [NICHD] and
National Heart, Lung, and Blood Institute [NHLBI] conducted a multicenter,
prospective, observational cohort study that involved 16 centers between 1994
and 1999. They enrolled 873 subjects who had mild asthma, 814 subjects who
had moderate asthma, 52 subjects who had severe asthma, and 881 nonasthmatic
controls. Because (1) prematurity is a leading cause of perinatal mortality and
long-term neurologic morbidity in children with very preterm births (b32 weeks’
gestation) account for most of the morbidity and mortality, and (2) asthma during
pregnancy has been associated with a fourfold increase of deliveries of less than
32 weeks’ gestation [9], preterm delivery of less than 32 weeks’ gestation was the
primary outcome of this study. Reporting on the perinatal outcomes in this study
in 2004, Dombrowski and colleagues [27] found no significant differences in the
rates of preterm delivery at less than 32 weeks’ gestation or at less than 37 weeks’
gestation. Of all of outcomes that were explored (including preterm delivery,
gestational diabetes, preeclampsia, preterm labor, chorioamnionitis, oligo-
hydramnios, cesarean delivery, low birth weight, small for gestational age, and
congenital malformations), only cesarean delivery rate was increased in the group
that had moderate to severe asthma (OR, 1.4; 95% CI, 1.1 –1.8). There were no
significant differences for neonatal outcomes, except for discharge diagnosis of
neonatal sepsis among the group that had mild asthma—a finding that may be
related to type 1 error. Among the cohort that had severe asthma, there was a
significantly increased incidence of gestational diabetes (OR, 3.0; 95% CI, 1.2–7.8)
and delivery at less than 37 weeks’ gestation (OR, 2.2; 95% CI, 1.2–4.2), after
adjusting for confounding variables by means of logistic regression analyses.
In a secondary analysis of this study, Schatz and colleagues [29] reported that
oral corticosteroid use was associated significantly with preterm delivery at less
than 37 weeks’ gestation (OR, 1.54; 95% CI, 1.02–2.33) and birth weight of less
than 2500 g (OR, 1.80; 95% CI, 1.13–2.88). In same cohort of patients, those
who had mild asthma had an exacerbation rate of 12.6% with a hospitalization
rate of 2.3% [30]. Those who had moderate asthma had an exacerbation rate of
25.7% and a hospitalization rate of 6.8%. Severe asthmatics (n = 52) had exac-
erbation and hospitalization rates of 51.9% and 26.9%, respectively. During the
course of pregnancy, 23.0% of women had an improvement in asthma severity,
88 dombrowski
and 30.3% had an increase in asthma severity. One of the most important
conclusions to be drawn from this study is that pregnant asthmatic patients, even
those who have mild or well-controlled disease, need to be monitored closely
during pregnancy.
The NICHD/NHLBI study had excellent maternal and perinatal outcomes,
despite a high frequency of asthma exacerbations. These findings do not con-
tradict the possibility that suboptimal control of asthma during pregnancy is
associated with an increased risk to the mother or baby. This study did find a
relationship between lower FEV1 during pregnancy and an increased risk of ges-
tational hypertension and prematurity [31]. The studies by Bracken and colleagues
[26] and Dombrowski and colleagues [27] suggest that if possible, asthma should
be controlled without oral corticosteroids. Both studies indicate that classification
of asthma severity with therapy that is tailored according to asthma severity can
result in excellent perinatal and maternal outcomes. This generally confirms the
findings of two earlier and smaller prospective cohort studies, in which the asthma
was managed by asthma specialists [13,14].
Putting the literature into perspective
There is considerable consistency among prospective studies of the effects

of asthma on maternal and perinatal outcomes. Eight prospective studies that
reported maternal and neonatal outcomes with at least 100 subjects, in locations at
or near sea level, have been published in the English literature (Table 1). One can
conclude from these studies that populations that have mild or moderate asthma
during pregnancy can have excellent maternal and perinatal outcomes. The two
largest studies, by Dombrowski and colleagues [27] and Bracken and colleagues
[26], reported an increase in preterm delivery at less than 37 weeks’ gestation
among subjects who had severe asthma or who required oral corticosteroids. In
addition, two studies reported an increase in preeclampsia [5,26], although one of
these only found this in patients who had daily symptoms [26]. Three studies
reported increased cesarean delivery [5,14,27], although one of these was only in
patients who had moderate to severe asthma [27]. One study reported an increased
incidence of gestational diabetes with severe asthma [27], and one found an
increased risk of SGAs in mothers who had daily asthma symptoms [26].
In contrast, there is much less consensus among retrospective studies of asthma in
pregnancy. Nearly every possible pregnancy complication has been associated with
asthma in at least one retrospective publication. Studies that enrolled patients after
the 1993 National Asthma Education and Prevention Program [NAEPP] rec-
ommendations [32] for anti-inflammatory management tended to have fewer ad-
verse pregnancy outcomes associated with asthma. This again supports the concept
that optimal asthma management can mitigate adverse pregnancy outcomes.
Patients who have poorly controlled asthma that is complicated by severe ex-
acerbations are at significant risk for maternal and fetal morbidity and mortality.
Table 1
Prospective cohort studies reporting obstetric and neonatal outcomes for pregnancies complicated by asthma
Dombrowski Bracken et al, Stenius-Aarniala Schatz et al, Mihrshahi et al, Jana et al, Stenius-Aarniala Minerbi-Codish
et al, 2004 [27] 2003 [26] et al, 1996 [14] 1995 [13] 1993 [22] 1995 [12] & Teramo, 1988 et al, 1998 [15]
(n = 1739) (n = 872) (n = 504) (n = 486) (n = 340) (n = 182) [5] (n = 181) (n = 101)
Preterm b32 weeks’ No
gestation
Preterm b37 weeks’ No (yes if severe) No (yes if oral No No No No No
gestation steroids)
Preeclampsia No No (yes if daily No No No Yes No
symptoms)
Cesarean delivery Yes (if moderate Yes, if elective No No Yes No
or severe)
Gestational diabetes No (yes if severe) No No No No
Small for gestational No No (yes if daily No No
age symptoms)
Malformation No No No No No
Antenatal hemorrhage No No No
Postnatal hemorrhage No
RDS/HMD No No No
outcomes of pregnancy in asthmatic women
NEC No No
Perinatal death No No No No No
NICU admission No No No No
Abbreviations: NEC, necrotizing enterocolitis; NICU, neonatal ICU; RDS/HMD, respiratory distress syndrome, hyaline membrane disease.
89
90 dombrowski
A potential explanation for the inconsistencies among previous studies with

regard to the effect of asthma on obstetric and neonatal outcomes is that many
studies of asthma during pregnancy did not classify asthma severity. Classi-
fication of asthma severity has important clinical implications with regard to
asthma morbidity and in tailoring optimal treatment regimens [32–34]. Failure
to classify severity may result in suboptimal asthma control, and thereby, increases
the risks for adverse maternal or neonatal outcomes. Oral corticosteroid treatment
may confound maternal and neonatal outcomes. Some positive findings may be
due to chance or confounders, such as ethnicity, smoking status, socioeconomic
status, and hypertension. Prospective studies may have had fewer significant
adverse associations because of better asthma surveillance and treatment.
There are important caveats when interpreting this literature. The excellent
maternal and perinatal outcomes of recent studies were achieved at centers that
tended to manage asthma actively in pregnancy. As described elsewhere in this
issue, NAEPP recommendations for active asthma management include step
therapy, anti-inflammatory treatment for gravidas who have persistent asthma,
assessment of pulmonary function by way of peak flow meters or spirometry,
patient education, and avoidance of asthma triggers. In addition, women who
enroll in research studies tend to be more compliant and better motivated than
the general public; compliance with prescriptions has been associated with better
outcomes among women who have asthma [21]. The lack of more adverse
outcomes among gravidas who have severe asthma also may be a function of
the small numbers of this subgroup, and the resulting lack of power to find
adverse outcomes that were statistically significant. Nonetheless, these prospec-
tive studies are reassuring in their consensus of good pregnancy outcomes among
women who have asthma. These studies do not suggest that asthma should be
considered to be a benign condition, because active asthma management was a
part of these studies.
Summary
Mild and moderate asthma can be associated with excellent maternal and
perinatal pregnancy outcomes, especially if patients are managed according to
contemporary NAEPP recommendations. Severe and poorly controlled asthma
may be associated with increased mild prematurity (b 37 weeks’ gestation), a
need for cesarean delivery, preeclampsia, and growth restriction. Poorly con-
trolled asthma and severe asthma exacerbations can result in maternal morbidity
and mortality, which can have commensurate adverse pregnancy outcomes.
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26 (2006) 93 – 102
Current Guidelines for the Management of

Asthma During Pregnancy
Jennifer Altamura Namazy, MDT, Michael Schatz, MD, MS
Department of Allergy, Kaiser Permanente Medical Center, 7060 Clairemont Mesa Boulevard,
San Diego, CA 92111, USA
Asthma is the most common, potentially serious medical problem to com-

plicate pregnancy. Studies have shown that pregnant asthmatic women have an
increased risk of adverse perinatal outcomes [1,2], whereas controlled asthma is
associated with reduced risks [3]. Managing asthma during pregnancy is unique
because the effect of the illness and the treatment on the developing fetus as well
as the patient must be considered.
The two main goals of asthma management during pregnancy are to opti-
mize maternal and fetal health. This article summarizes specific studies and
recently published guidelines regarding the optimal management of asthma
during pregnancy.
Prevalence of asthma during pregnancy
Previous estimates of asthma prevalence during pregnancy were between 4%

and 7% [1–5]. Many of these reports were from retrospective data, rather
than being based on a nationally representative sample. Recently, Kwon and
colleagues [6] reviewed U.S. national health surveys spanning 1997 to 2001. The
aim was to determine more definitively the prevalence of asthma in pregnant
women ages 18 to 44. Time trends also were examined using health surveys from
1976 to 1980 and 1988 to 1994. They found that asthma affected between 3.7%
and 8.4% of pregnant women in the United States between 1997 and 2001. There
E-mail address: janamazy@yahoo.com (J.A. Namazy).
94 namazy & schatz
was a twofold increase in the prevalence of asthma (from 2.9% to 5.8%) be-
tween 1976 and 1980 and 1988 and 1994. This study supports initial prevalence
estimates, but also suggests that they may have been conservative. More im-
portantly, this study supports the observation that asthma affects more pregnant
women each year.
Effects of uncontrolled asthma on pregnancy
The potential effects of asthma on the course of pregnancy are reviewed

elsewhere in this issue. Observations that support the hypothesis that un-
controlled asthma increases perinatal risks, whereas controlled asthma reduces
these risks form an important basis for the management recommendations in this
article. For example, studies have shown that better controlled asthma (defined by
lack of acute episodes or higher maternal pulmonary function) leads to improved
intrauterine growth (measured by birth weight or ponderal indices [7–10]. In
contrast, patients who have daily asthma symptoms are at increased risk for
intrauterine growth retardation and preeclampsia [11,12].
Asthma management during pregnancy: nonpharmacologic
The general principles of asthma management during pregnancy do not differ

substantially from the management of nonpregnant asthmatics. The ultimate goal
for the pregnant asthmatic is to have no limitation of activity, minimal chronic
symptoms, no exacerbations, normal pulmonary function, and minimal adverse
effects of medications. It is the clinician’s job to provide optimal therapy to
maintain asthma control that improves maternal quality of life and allows for
normal fetal maturation.
Assessment and monitoring
Objective assessments and monitoring should be performed on a monthly

basis. Such assessments should include pulmonary function testing (ideally spi-
rometry), detailed symptom history (symptom frequency, nocturnal asthma,
interference with activities, exacerbations, and medication use), and physical
examination with specific attention paid to auscultation of the lungs. Schatz and
colleagues [13] observed that 30% of subjects whose asthma was classified as
mild at entry ‘‘switched’’ categories during pregnancy to the moderate or severe
groups. Thus, pregnant asthmatic patients, even those who have mild or well-
controlled disease, need to be monitored closely during pregnancy [13]. It also
was observed that patients with a forced expiratory volume in 1 second (FEV1)
of less than 80% of predicted are at increased risk of asthma morbidity [13] and
management of asthma during pregnancy 95
pregnancy complications [14]. Home peak flow monitoring may be a valuable

tool in managing the pregnant asthmatic who has moderate to severe disease.
Because asthma has been associated with intrauterine growth retardation and
preterm birth, it is useful to establish pregnancy dating accurately by a first
trimester ultrasound. Patients should be instructed to be attentive to fetal activ-
ity. Some women may benefit from additional evaluation of fetal activity and
growth by serial ultrasound examinations. According to current guidelines,
women who have moderate to severe asthma or suboptimally controlled asthma,
or who are recovering from a severe exacerbation are candidates for antenatal
surveillance [15].
There should be open lines of communication with the patient’s obstetrician.
Obstetricians should be involved in asthma care and should obtain information on
asthma status during prenatal visits.
Avoidance of asthma triggering factors
Avoidance of asthma triggers, such as animal dander, tobacco smoke, and

pollutants, is important because exposure may lead to increased asthma symp-
toms and the potential need for more medication. Often, allergen immunotherapy
is effective for those patients in whom symptoms persist, despite optimal envi-
ronmental control and proper drug therapy. Allergen immunotherapy can be
continued carefully during pregnancy in patients who are deriving benefit, who
are not experiencing systemic reactions, and who are receiving maintenance
doses. Benefit–risk considerations do not generally favor beginning immunother-
apy during pregnancy for most patients because of (1) the undefined propensity
for systemic reactions, (2) the increased likelihood of systemic reactions during
initiation of immunotherapy, (3) the latency of immunotherapy effect, and (4) the
frequent difficulty in predicting which asthmatic patients will benefit from im-
munotherapy [15].
Smoking should be discouraged strongly, and all patients should try to avoid
environmental tobacco smoke exposure as much as possible. Morbidity dur-
ing pregnancy that is due to smoking may be independent of, and additive to,
morbidity that is due to asthma [8].
Patient education
Patient education is more important than ever during pregnancy. The patient
must understand the potential adverse effects of uncontrolled asthma on the well-
being of the fetus, and that treating asthma with medications is safer than in-
creased asthma symptoms that may lead to maternal and fetal hypoxia. Above all,
she should be able to recognize symptoms of worsening asthma and be able to
treat them appropriately. This requires an individualized action plan that is based
on a joint agreement between the patient and the clinician. Correct inhaler
technique should be assured, and the patient also should understand how she can
reduce her exposure to, or control those, factors that exacerbate her asthma.
96 namazy & schatz
Updated guidelines for the pharmacologic management of asthma during

pregnancy
General information regarding the safety of medications during pregnancy and

gestational data for specific asthma and allergy medications are summarized
elsewhere in this issue. In 1993, the National Asthma Education and Prevention
Program Expert Panel Report (NAEPP) published the Report of the Working
Group on Asthma and Pregnancy [16], which reviewed the data from available
studies, and presented recommendations for the pharmacologic management of
asthma during pregnancy. Since then there have been new developments, includ-
ing the introduction of new medications, the availability of additional safety data,
and revisions to severity classification and treatment guidelines in the general
management of asthma [17,18]. All of these developments led to an update of the
1993 report which was published recently: NAEPP Working Group Report on
Managing Asthma During Pregnancy: Recommendations for Pharmacologic
Treatment—Update 2004 [15]. The focus of this update was to review new data
regarding the safety and effectiveness of asthma medications taken during preg-
nancy and lactation. Although this report presents an extensive review of the
current literature with specific recommendations, the working group members
stress that these guidelines are meant to assist clinical decision-making and
should be used adjunctively when designing a treatment plan that is tailored
specifically to the needs of a pregnant patient.
There are several differences between the recommendations that were made in
the 1993 report, the 2002 EPR-2 update [18], and the recent update in 2004. The
1993 report recommended that controller therapy for moderate asthma (which
included what was later defined as mild or moderate persistent asthma) be
initiated with cromolyn because of its safety profile. Since then, strong evidence
demonstrates that cromolyn is not as effective as inhaled corticosteroids for
the treatment of persistent asthma, and new information regarding the safety of
inhaled corticosteroids has been published [18]. Therefore, inhaled steroids are
recommended as the preferred controller therapy for all levels of persistent
asthma. Compared with the EPR-Update in 2002, the most important difference
is that two equal treatment options are recommended for moderate persistent
asthma: a combination of low-dose inhaled corticosteroids plus a long-acting
b-2 agonist, or medium-dose inhaled corticosteroids.
Effectiveness of inhaled corticosteroids during pregnancy
Inhaled corticosteroids are well documented to prevent asthma exacerbations

in nonpregnant women. This also is true in the pregnant population as reported
by Stenius-Aarniala and colleagues [19]. They found a higher incidence of asthma
exacerbations in those who were not treated initially with inhaled corticosteroid
in comparison with patients who had been on an inhaled corticosteroid from the
beginning of pregnancy. In addition, two randomized controlled trials during

pregnancy support the efficacy of inhaled steroids during pregnancy [20,21].
First, a prospective randomized controlled trial studied 72 pregnant asthmatics
who presented to an emergency department or prenatal clinic with an asthma
exacerbation. There was a 55% reduction in exacerbations and readmissions in
women who were given inhaled beclomethasone dipropionate with oral cortico-
steroids and b-2 agonists compared with women who were treated with oral
corticosteroids and b-2 agonists alone [20].
Second a prospective, double-blind, double placebo-controlled randomized
clinical trial that was published recently by Dombrowski and colleagues [21]
compared the efficacy of inhaled beclomethasone dipropionate with oral the-
ophylline for the prevention of asthma exacerbations during pregnancy. There
was no significant difference in the proportion of asthma exacerbations among
the 194 women who used beclomethasone dipropionate versus the 191 women
who took theophylline. There were fewer reported side effects, less discontinua-
tion of medication, and a lower proportion of women with FEV1 less than 80% in
the group that used beclomethasone dipropionate. This study supports previous
guidelines that inhaled corticosteroids are the therapy of choice for persistent
Choice of specific medications during pregnancy
Inhaled corticosteroids
In 1993, the Working Group on Asthma and Pregnancy stated that cortico-
steroids are the most effective anti-inflammatory drugs for the treatment of
asthma. At that time, beclomethasone dipropionate, triamcinolone, and fluniso-
lide were recognized as treatment options; there was the most experience during
pregnancy with beclomethasone dipropionate. Therefore, it was recommended
as the inhaled corticosteroid of choice at that time [16]. Publications since then
have supported the overall safety of inhaled corticosteroid use in pregnancy; the
most safety data are available for inhaled budesonide. Thus, in the current
guidelines, budesonide is the preferred inhaled corticosteroid during pregnancy.
The recent guidelines emphasize that there are no data to suggest that other
inhaled corticosteroids are less safe during pregnancy. Thus, if a pregnant asth-
matic woman is using an alternative inhaled corticosteroid before pregnancy and
her asthma is well controlled, it would not be unreasonable to continue it through
the pregnancy.
Oral corticosteroids
Data regarding the use of systemic corticosteroids during pregnancy have not
been totally reassuring. Recent available human studies include a meta-analysis
of 6 cohort studies by Park-Wyllie and colleagues evaluating the relationship
98 namazy & schatz
between corticosteroid use during pregnancy and congenital malformations, and

four case-control studies evaluating the potential relationship between systemic
corticosteroid use during pregnancy and oral clefts [22]. They found that while
there was no definite increased risk of total congenital malformations, there was a
statistically significant increased risk of oral clefts in infants of mothers treated
with corticosteroids during the first trimester (summary odds ratio [OR], 3.35;
95% confidence interval, 1.97–5.69).
Other adverse outcomes that recently were associated with systemic cortico-
steroid use during pregnancy include preeclampsia, low birth weight, and preterm
delivery [9,23–25]. The available data make it difficult to separate the effects of
the corticosteroids on these outcomes from the effects of severe or uncontrolled
asthma. It must be stressed that the potential risks of oral corticosteroid use
during pregnancy must be balanced against the risks to the mother and infant of
poorly managed severe disease, which include maternal mortality, fetal mortality,
or both [15]. The current recommendations support the use of oral corticosteroids
when indicated for the long-term management of severe asthma or for severe
exacerbations during pregnancy [15].
Short-acting bronchodilators
The 1993 guidelines did not make a recommendation regarding a specific

short-acting inhaled b-agonist for use during pregnancy [16]. Based on the data
that have been published since then, albuterol is recommended as the inhaled,
short-acting b-agonist of choice during pregnancy [15].
Long-acting b-agonists
Since 1993, two long-acting inhaled bronchodilators have become available—

salmeterol and formoterol. There are few published data regarding the safety of
these drugs during pregnancy. The new guidelines recommend salmeterol as
the long-acting b-agonist of choice during pregnancy because it has been avail-
able for a longer period of time in this country [15].
Other medications
The 1993 report recognized the use of nebulized ipratropium in women

who presented with acute asthma who do not improve substantially with the
first inhaled b-agonist treatment. Since then, there have been no further published
data on anticholinergics in pregnancy, but this recommendation is maintained
in the updated guidelines [15]. Other medications are recommended only as
alternative, but not preferred, choices during pregnancy. These include cromolyn
(for mild persistent asthma), theophylline (for mild persistent asthma or as
add-on therapy to inhaled corticosteroids), and zafirlukast or montelukast

(for mild persistent asthma or as add-on therapy to inhaled corticosteroids).
The serum concentrations of theophylline need to be monitored closely, and low-
dose therapy is recommended with maintenance serum levels targeted at 5 to
12 mg/mL.
Pharmacologic step therapy during pregnancy
Many pregnant asthmatic women require medications to control their asthma.

Current guidelines recommend a generalized stepwise approach (Table 1) in
achieving and maintaining asthma control. The number and dose of medications
used are increased as necessary and decreased when possible. Decreasing doses
should be done carefully because this may lead to an exacerbation of symp-
toms. Current guidelines suggest that it may be prudent to postpone attempts
at reducing therapy that is controlling the patient’s asthma until after the in-
fant’s birth.
The classification of asthma severity as outlined in the current guidelines
also may help to predict asthma morbidity during pregnancy. Schatz and col-
leagues [13] reported that asthma morbidity (hospitalizations, office visits, oral
corticosteroid use) correlated closely with asthma classification applied to the
Table 1
Stepwise approach for the management of chronic asthma during pregnancy
Category Step therapy
Mild intermittent Inhaled b-agonist as neededa
Mild persistent Low-dose inhaled corticosteroidb
Alternative: cromolyn, leukotriene receptor antagonist, or theophyllinec
Moderate persistent Low-dose inhaled corticosteroid and long-acting b-agonistd
or medium-dose inhaled corticosteroid
or (if needed) medium-dose inhaled corticosteroid and long-acting b-agonist
Alternative: low-dose or (if needed) medium-dose inhaled corticosteroid and
either theophylline or leukotriene receptor antagonist
Severe persistent High-dose inhaled corticosteroid and long-acting b-agonist and, if needed,
oral corticosteroids
Alternative: High-dose inhaled corticosteroid and theophylline
Based on the recommendations of the National Asthma Education Program Report of the Working
Group on Asthma During Pregnancy Update 2004 [15].
a
More published human data on using albuterol during pregnancy than on using other short-
acting b-agonists.
b
More data on using budesonide than on using other inhaled corticosteroids.
c
Maintain to serum concentration of 5–12 mg/mL.
d
Salmeterol is considered the long-acting b-agonist of choice during pregnancy because of its
longer availability in this country.
100 namazy & schatz
subjects at entry (ie, subjects who had mild asthma experienced fewer hospitali-
zations, unscheduled visits, oral corticosteroid courses, and total exacerbations
than those who had moderate asthma; subjects who had severe asthma at entry
experienced the greatest risk of asthma morbidity during pregnancy).
Management of acute exacerbations of asthma during pregnancy
A recent large multicenter study reported that 20% of women who have
persistent asthma experienced an unscheduled (emergency department or physi-
cian) visit for asthma during pregnancy, and 8% required hospitalization [13].
Such exacerbations can compromise fetal well-being; therefore, aggressive home
management of acute symptoms needs to be reviewed with pregnant asthmatic
patients. Above all, pregnant asthmatic patients should be taught to recognize
the early signs and symptoms of exacerbations. The current recommendations
for home and emergency department management of asthma exacerbations in
pregnant asthmatic women are not different from the EPR-2 [17] recommenda-
tions in nonpregnant asthmatic women that were published previously. These
guidelines are reviewed in detail elsewhere in this issue.
Management of asthma during labor and delivery
Only approximately 10% to 20% of women develop an exacerbation of

asthma during labor and delivery [13,26]. Nonetheless, asthma medications
should be continued during labor and delivery. If a systemic steroid has been used
in the previous month, then stress-dose steroid should be administered during
labor to prevent maternal adrenal crisis. Practitioners should be aware of the
potential side effects that labor medications that are used commonly may have
on asthma. For instance, prostaglandin F2 alpha and methylergonovine, which are
used for postpartum hemorrhage, can induce bronchospasm. Prostaglandin E2
and magnesium sulfate may be used safely in asthmatic patients. Maternal and
fetal hypoxia that is due to asthma during labor and delivery can be managed
medically. It is rarely necessary to perform an emergent caesarean section.
Summary
Over the past few years, much has been learned that is relevant to the man-
agement of asthma in pregnancy. Although the studies that were reviewed herein
provide more insight into the mechanisms that are involved and the treatment of
asthma during pregnancy, there are more questions to be answered. It is hoped
that the updated guidelines, which address the safety of contemporary asthma
medications during pregnancy, will be a helpful resource in the treatment of our
pregnant asthmatic patients.
References
[1] Clark SL, National Asthma Education Program Working Group on Asthma and Pregnancy,
National Institutes of Health, National Heart, Lung, and Blood Institute. Asthma in pregnancy.
Obstet Gynecol 1993;82:1036 – 40.
[2] Schatz M. Asthma during pregnancy: interrelationships and management. Ann Allergy 1992;
68:123 – 32.
[3] Derbes VJ. Reciprocal influences of bronchial asthma and pregnancy. Am J Med 1946;1:
367 – 75.
nancy. Obstet Gynecol 1998;92:435 – 40.
[5] Greenberger PA. Management of asthma during pregnancy. N Engl J Med 1985;312:897 – 902.
[6] Kwon H, Belanger K, Bracken MB. Asthma prevalence among pregnant and childbearing-aged
13:317 – 24.
[7] Schatz M, Dombrowski M. Outcomes of pregnancy in asthmatic women. Immunol Allergy
Clin North Am 2000;20:715 – 21.
[8] Schatz M, Zeiger RS, Hoffman CP. Intrauterine growth is related to gestational pulmonary
function in pregnant asthmatic women. Chest 1990;98:389 – 92.
[9] Jana N, Vasishta K, Saha SC, et al. Effect of bronchial asthma on the course of pregnancy,
labour and perinatal outcome. J Obstet Gynaecol 1995;21(3):227 – 32.
[10] Fitzsimons R, Greenberger PA. Outcome of pregnancy in women requiring corticosteroids for
severe asthma. J Allergy Clin Immunol 1986;78:349 – 53.
[12] Triche EW, Saftlas AF, Belanger K, et al. Association of asthma diagnosis, severity, symptoms,
and treatment with risk of preeclampsia. Obstet Gynecol 2004;104(3):585 – 93.
by severity classification. J Allergy Clin Immunol 2003;112:283 – 8.
[14] Schatz M, Dombrowski MP, Wise R, et al. Spirometry is related to perinatal outcomes in
pregnant asthmatic women. Am J Obstet Gynecol, in press.
[15] Asthma and pregnancy—update 2004. NAEPP Working Group Report on Managing Asthma
During Pregnancy: recommendations for pharmacologic treatment-update 2004. Bethesda (MD):
US Department of Health and Human Services; 2005. Publication #NIH 05–3279.
[16] Asthma and pregnancy report. NAEPP report of the Working Group on Asthma and Pregnancy:
management of asthma during pregnancy. Bethesda (MD)7 US Department of Health and Human
Services; 1993. Publication #NIH 93–3279.
[17] NAEPP expert panel report 2: guidelines for the diagnosis and treatment of asthma. Bethesda
(MD)7 US Department of Health and Human Services; 1997. Publication #NIH 97–4051.
[18] NAEPP expert panel report: guidelines for the diagnosis and treatment of asthma – update
on selected topics 2002. Bethesda (MD)7 US Department of Health and Human Services; 2003.
Publication #NIH 02–5074.
[19] Stenius-Aarniala BS, Hedman J, Teramo KA. Acute asthma during pregnancy. Thorax 1996;
51(2):411 – 4.
[20] Wendel PJ, Ramin SM, Barnett-Hamm C, et al. Asthma treatment in pregnancy: a randomized
controlled study. Am J Obstet Gynecol 1996;175(1):150 – 4.
[21] Dombrowski MP, Schatz M, Wise R, et al. Randomized trial of inhaled beclomethasone
102 namazy & schatz
dipropionate versus theophylline for moderate asthma during pregnancy. Am J Obstet Gynecol
2004;190:737 – 44.
[22] Park-Wyllie L, Mazzotta P, Pastuszak A, et al. Birth defects after maternal exposure to
corticosteroids: prospective cohort study and meta-analysis of epidemiological studies. Tera-
tology 2000;62(6):385 – 92.
[23] Schatz M, Zeiger RS, Harden K, et al. The safety of asthma and allergy medications during
pregnancy. J Allergy Clin Immunol 1997;100:301 – 6.
[24] Perlow JH, Montgomery D, Morgan MA, et al. Severity of asthma and perinatal outcome.
Am J Obstet Gynecol 1992;167(4 Pt 1):963 – 7.
[25] Cydulka RK, Emerman CL, Schreiber D, et al. Acute asthma among pregnant women present-
ing to the emergency department. Am J Respir Crit Care Med 1999;160(3):887 – 92.
[26] Schatz M, Harden K, Forsythe A, et al. The course of asthma during pregnancy, post partum,
and with successive pregnancies: a prospective analysis. J Allergy Clin Immunol 1988;81(3):
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26 (2006) 103 – 117
Acute Asthma During Pregnancy

Rita K. Cydulka, MD, MS
MetroHealth Emergency Medicine, 2500 MetroHealth Drive, Cleveland, OH 44109-1998, USA
The prevalence of asthma in pregnant women will increase as the prevalence

of asthma in the general population increases [1]. Many of these patients will
suffer acute asthma during pregnancy. A prospective study from Finland sug-
gested that 9.3% of 504 pregnant women who had asthma and who were fol-
lowed in a pulmonary clinic required emergency treatment for asthma during
pregnancy [2]. A more recent and larger prospective study from this country
included 1739 pregnant asthmatic women who were followed in obstetric clinics;
5.1% of patients were hospitalized and 15.8% required an unscheduled visit for an
asthma exacerbation during pregnancy [3]. These exacerbations were more
common in patients who had persistent asthma and were especially common in
patients who had severe persistent asthma, 26.9% of whom required a hospital-
ization and 36.5% had an unscheduled visit for acute asthma during pregnancy.
Data indicate that the course of asthma during pregnancy improves in one
third, worsens in one third, and remains unchanged in one third [4–9]. Asthma
symptoms and exacerbations tend to peak during the second trimester [3,4,7–9].
In the study from Finland, exacerbations occurred most frequently between 17
and 24 weeks of pregnancy [2]. Exacerbation during labor and delivery is
uncommon, usually is treated easily, and is more likely to occur in patients in
whom asthma is controlled inadequately or in those who acquire an infection [8].
Limited data suggest that pregnant asthmatic African American women
experience more morbidity than do white women. They are 1.35 times more
likely to receive a course of rescue corticosteroids, 1.89 times more likely to visit
an emergency department, and 1.73 times more likely to be hospitalized during
pregnancy [10].
Asthma exacerbations can harm the fetus in several ways. Poor control of
asthma during pregnancy is associated with several poor outcomes for mother
E-mail address: rcydulka@metrohealth.org
104 cydulka
and baby, including perinatal mortality, preeclampsia, preterm birth, and low birth
weight [9,11–15]. Maternal hypoxia may cause fetal hypoxia directly [16,17]. In
addition, other consequences of poorly controlled asthma, such as hypocapnia
and alkalosis, may cause fetal hypoxia indirectly by reducing uretoplacental
blood flow [16,17]. Therefore, acute asthma exacerbations during preg-
nancy should be managed aggressively in the home, emergency department,
and hospital.
Treatment goals
Home management of asthma exacerbations
Pregnant asthmatics must be admonished to be diligent in monitoring their

asthma symptoms and vigilant in recognizing early signs and symptoms of acute
asthma exacerbation. An increase in cough, the appearance of chest tightness,
dyspnea, wheezing, decrease in fetal movement, or a 20% decrease in peak
expiratory flow rate (PEFR) may signal the worsening of asthma and should
warrant immediate attention. All patients should have a personal action plan for
initiating home therapy and for seeking medical attention [18].
The goal of treatment is prevention of maternal and fetal hypoxia and quick
reversal of airway obstruction. An algorithm for home therapy is presented
in Fig. 1. Home treatment should begin with inhaled b-2 agonist treatment
(eg, albuterol, two to four puffs or single nebulizer treatments every 20 minutes
for up to 1 hour). Quick resolution of symptoms, ability to resume normal
activity, and return of PEFR to greater than 80% of personal best indicate a good
response. Prompt further medical attention, such as a visit to the doctor or
emergency department, is indicated if there is an incomplete response to initial
therapy or a decrease in fetal movement.
Emergency department and physician/hospital-based management
Emergency department and other acute interventions should be guided by

pulmonary function tests (forced expiratory volume in 1 second [FEV1], PEFR),
vital signs, chest and heart examinations, and the patient’s subjective assessment
of dyspnea. The goals of emergency treatment are to ensure adequate oxygena-
tion for mother and fetus and to relieve airflow obstruction. An ideal therapy
does not exist, and the use of multidrug regimens is common. Supplemental
oxygen, inhaled b-2 agonists, systemic corticosteroids, and, when indicated,
inhaled anticholinergic agents are the mainstays of asthma treatment in the
emergency department.
An algorithm that outlines recommendations for assessment and care of acute
asthma exacerbation in the emergency department and hospital is presented in
acute asthma during pregnancy 105
Fig. 1. Home management of acute asthma exacerbation during pregnancy. From National Asthma
Education and Prevention Program Working Group report on managing asthma during pregnancy.
Recommendations for pharmacologic treatment. Bethesda (MD): US Department of Health and
Human Services, National Institutes of Health, National Heart, Lung, and Blood Institute; 2005. p. 53.
NIH Publication #05–5236.
Fig. 2. Medications and dosages for acute asthma exacerbations are presented in
Table 1. The safety of medications during pregnancy is discussed elsewhere in
this issue. A recent review of the literature indicates that human gestational
studies have been conducted for the inhaled corticosteroids (ICSs), beclometha-
sone, budesonide, and triamcinolone, and for cromolyn sodium, theophylline, and
salmeterol [19]. No asthma medication has been placed in category A, which
106 cydulka
Fig. 2. Emergency department/hospital-based management of acute asthma exacerbation during

pregnancy. From National Asthma Education and Prevention Program Working Group report on
managing asthma during pregnancy. Recommendations for pharmacologic treatment. Bethesda (MD):
US Department of Health and Human Services, National Institutes of Health, National Heart, Lung,
and Blood Institute; 2005. p. 54. NIH Publication #05–5236.
requires adequate and controlled human data and reassuring animal studies.
Human pregnancy data support a U.S. Food and Drug Administration pregnancy
category B rating for budesonide. Pregnancy category B ratings for cromolyn,
nedocromil, montelukast, and zafirlukast are based primarily on safety in animal
reproduction studies. ICSs other than budesonide, theophylline, zileuton, and
long-acting b-2 adrenergic agonists are pregnancy category C. Human pregnancy
data for many asthma controllers are lacking; nonetheless, data support a range of
choices among medications that are rated pregnancy category B [19].
Assessment
The goal of therapy is prevention of maternal and fetal hypoxia [16,17]. A
focused history and physical examination should be performed rapidly and
treatment should be initiated promptly. Attention to vital signs and work of
breathing should be supplemented with objective measures of response to
therapy, such as assessment of oxygen saturation and FEV1 or PEFR. If possible,
fetal monitoring should be performed once the fetus is potentially viable because
it may provide an early indicator of fetal distress.
Oxygen should be administered as needed to maintain oxygen saturation (SpO2)
of at least 95% saturation. Hypoxemia is not common during most acute asthma
exacerbations [20,21]. Arterial blood gas measurements need to be obtained only
in patients who experience severe or prolonged attacks. In the nonpregnant
patient, hypercapnia, severe hypoxemia, or metabolic acidosis does not occur
until the PEFR or FEV1 is less than 25% of predicted values [22–24]. The degree
of hypoxemia that is determined by arterial blood gas generally reflects the extent
of ventilation–perfusion mismatch. As pregnancy progresses, the normal PaCO2
decreases to 27 to 32 mm Hg [16]. Thus, a Paco2 of more than 35 mm Hg
indicates severe airway obstruction and impending ventilatory failure during
pregnancy, and needs to be addressed immediately.
A chest radiograph is necessary only if pneumonia, pneumothorax, pneumo-
mediastinum or other pulmonary pathology is suspected or if the patient fails to
respond to aggressive bronchodilator therapy [25,26]. Generally, electrocardiog-
raphy is not helpful, except to rule out suspected cardiac problems. Blood tests,
including a complete blood count, also are unlikely to help guide the acute
management of an asthma attack.
Treatment
b-2 Agonists. b-2 agonists relax airway smooth muscle by stimulating b-2
receptors and increasing cyclic cAMP. Data from human studies indicate that
the use of b-2 agonists are safe during pregnancy [27–30]. Treatment should
be initiated with a b-2 agonist, such as albuterol, 2.5 to 5.0 mg delivered
by nebulizer or MDI with spacing device every 20 minutes for three doses, or
continuously at 10 to 15 mg/h if obstruction is severe. Current evidence indicates
that administration by nebulizer and multi-dose inhaler (MDI) with spacer are
108
Table 1
Medications and dosages for asthma exacerbation during pregnancya
Medications Adult dose Child dose Comments
Short-acting inhaled beta2-agonists
Albuterol
Nebulizer solution (5.0 mg/mL, 2.5–5 mg every 20 minutes for 0.15 mg/kg (minimum dose 2.5 mg) Only selective beta2-agonists are rec-
2.5 mg/3mL, 1.25 mg/3mL, 3 doses, then 2.5–10 mg every every 20 minutes for 3 doses, then ommended. For optimal delivery,
0.63 mg/3 mL) 1–4 hours as needed, or 0.15–0.3 mg/kg up to 10 mg every dilute aerosols to minimum of 3 mL
10–15 mg/hour continuously 1–4 hours as needed, or 0.5 mg/kg/hour at gas flow of 6–8 L/min.
by continuous nebulization
cydulka
MDI (90 mg/puff) 4–8 puffs every 20 minutes up to 4–8 puffs every 20 minutes for 3 doses, As effective as nebulized therapy if
4 hours, then every 1–4 hours then every 1–4 hours inhalation patient is able to coordinate.
as needed maneuver; use spacer/holding chamber
Bitolterol
Nebulizer solution (2 mg/mL) See albuterol dose. See albuterol dose, thought to be half as Has not been studied in severe
potent as albuterol on a mg basis. asthma exacerbations. Do not mix
with other drugs.
MDI (370 mg/puff) See albuterol dose. See albuterol dose. Has not been studied in severe
asthma exacerbations.
Levalbuterol (R-albuterol)
Nebulizer solution 1.25–2.5 mg every 20 minutes for 0.075 mg/kg (minimum dose 1.25 mg) 0.63 mg of levalbuterol is equivalent
(0.63 mg/3 mL, 1.25 mg/3 mL) 3 doses, then 1.25–5 mg every every 20 minutes for 3 doses, then to 1.25 mg of racemic albuterol for
1–4 hours as needed, or 0.075–0.15 mg/kg up to 5 mg every both efficacy and side effects.
5–7.5 mg/hour continuously 1–4 hours as needed, or 0.25 mg/kg/hour
by continuous nebulization
Pirbuterol
MDI (200 mg/puff) See albuterol dose. See albuterol dose, thought to be half as Has not been studied in severe
potent as albuterol on a mg basis. asthma exacerbations.
Systemic (injected) beta2-agonists

Epinephrine
1:1000 (1 mg/mL) 0.3–0.5 mg every 20 minutes for 0.01 mg/kg up to 0.3–0.5 mg every No proven advantage of systemic
3 doses sq 20 minutes for 3 doses sq therapy over aerosol.
Terbutaline (1 mg/mL) 0.25 mg every 20 minutes for 0.01 mg/kg every 20 minutes for No proven advantage of systemic
3 doses sq 3 doses, then every 2–6 hours as therapy over aerosol.
needed sq
Anticholinergics
Ipratropium bromide
Nebulizer solution (0.25 mg/mL) 0.5 mg every 30 minutes for 3 doses, 0.25 mg every 20 minutes for 3 doses, May mix in same nebulizer with
then every 2–4 hours as needed then every 2 to 4 hours albuterol. Should not be used as
first-line therapy; should be added to
beta2-agonist therapy.
MDI (18 mg/puff) 4–8 puffs as needed 4–8 puffs as needed Dose delivered from MDI is low and
has not been studied in asthma
exacerbations.
Ipratropium with albuterol
acute asthma during pregnancy
Nebulizer solution (Each 3 mL 3 mL every 30 minutes for 3 doses, 1.5 mL every 20 minutes for 3 doses, Contains EDTA to prevent discolor-
vial contains 0.5 mg ipratropium then every 2–4 hours as needed then every 2–4 hours ation. This additive does not induce
bromide and 2.5 mg albuterol) bronchospasm.
MDI (Each puff contains 18 mg 4–8 pufs as needed 4–8 puffs as needed
ipratropium bromide and
90 mg albuterol)
(continued on next page)
109
110
Table 1 (continued)
Medications Adult dose Child dose Comments
Systemic corticosteroids (Dosages and comments apply to all three corticosteroids)
Prednisone 120–180 mg/day in 3 or 4 divided 1 mg/kg every 6 hours for 48 hours, then For outpatient ‘‘burst’’ use 40–60 mg
Methylprednisolone doses for 48 hours, then 60–80 mg/day 1–2 mg/kg/day (maximum = 60 mg/day) in single or 2 divided doses for adults
Prednisolone until PEF reaches 70% of predicted in 2 divided doses until PEF is 70% of (children: 1–2 mg/kg/day, maximum
or personal best predicted or personal best 60 mg/day) for 3–10 days.
The most important determinant of appropriate dosing is the clinician’s judgment of the patient’s reponse to therapy.
No advantage has been found for higher dose corticosteroids in severe asthma exacerbations, nor is there any advantage for intravenous administration over oral therapy
cydulka
provided gastrointestinal transit time or absorption is not impaired. The usual regimen is to continue the frequent multiple daily dose until the patient achieves an FEV1 or
PEF of 50 percent of predicted or personal best and then lower the dose to twice daily. This usually occurs within 48 hours. Therapy following a hospitalization or
emergency department visit may last from 3 to 10 days. If patients are then started on inhaled corticosteroids, studies indicate there is no need to taper the systemic
corticosteroid dose. If the followup systemic corticosteroid therapy is to be given once daily, one study indicates that it may be more clinically effective to give the dose in
the afternoon at 3 pm, with no increase in adrenal suppression.
a
Adapted from EPR—Update 2002.
From National Asthma Education and Prevention Program Working Group report on managing asthma during pregnancy. Recommendations for pharmacologic treatment.
Bethesda (MD): US Department of Health and Human Services, National Institutes of Health, National Heart, Lung, and Blood Institute; 2005. NIH Publication #05–
5236; Appendix B; p. 55.
equivalent [31,32]. Continuous therapy may offer a slight advantage in patients

who have severe obstruction [33,34].
Systemic corticosteroids. All patients should receive systemic corticosteroids—

preferably oral—early in their treatment regimen, because data indicate that
patients who receive glucocorticoids early require fewer hospital admissions and
sustain fewer relapses after discharge from the emergency department [35].
Studies have revealed conflicting evidence about the safety of oral corticosteroids
during pregnancy [15,27,29,36–39]. Oral corticosteroid use during the first
trimester seems to be associated with a slight increased risk for oral clefts. It is
difficult to separate the other adverse effects that are associated with cortico-
steroid use, such as preeclampsia, preterm delivery, and low birth weight, from
the effects of uncontrolled asthma. Systemic corticosteroids may be withheld in
patients who immediately and completely respond to b-2 agonists or in those who
took an adequate dose of systemic corticosteroids before arrival for medical care.
Intravenous corticosteroids should be administered to patients who have
impending respiratory failure to ensure adequate absorption. Studies to support
the use of high-dose ICSs in lieu of systemic corticosteroids during acute asthma
exacerbation in pregnancy are lacking, and therefore, they cannot be recom-
mended [35,40–42].
Ipratropium bromide. Ipratropium bromide is a quaternary amine anticholiner-

gic agent that is minimally absorbed from the lungs [43]. Data from multiple
studies indicated that the addition of ipratropium to b-2 agonist agents resulted in
modest improvement in bronchodilation and decreased need for hospitalization
among patients who presented with severe obstruction [44–46]. Although there
are no published data on the use of anticholinergic agents in pregnancy, the
National Asthma Education and Prevention Program (NAEPP) Working Group
on Asthma in Pregnancy recommends the use of ipratropium bromide during
acute asthma exacerbation [47–51].
Other asthma medications. Nedocromil and cromolyn inhibit the release of

inflammatory cytokines from mast cells, but they have no role in acute man-
agement. The role of leukotriene modifiers in acute asthma exacerbation has yet
to be defined. Two studies, one using intravenous montelukast [52] and the other
using oral zafirlukast [53], demonstrated some benefit of leukotriene receptor
antagonist therapy when added to standard therapy during emergency care.
Leukotriene modifiers have not been studied in the treatment of acute asthma
exacerbations during pregnancy. The benefits of ketamine and halothane remain
largely anecdotal; they have not been substantiated in controlled trials and have
not been studied in pregnant asthmatics [47–50].
Magnesium sulfate. Magnesium sulfate, a physiologic regulator of intracellular

calcium flux, is an effective bronchodilator. In addition to preventing histamine
release from mast cells and opposing the action of acetylcholine, magnesium
112 cydulka
directly inhibits bronchial smooth muscle contraction. High-dose magnesium has

been used as a treatment for eclampsia for decades [54,55]. Although only a
single case report has documented the use of intravenous magnesium in the
treatment of severe asthma in pregnancy [56], substantial evidence exists to
support its use in severely obstructed nonpregnant asthmatic patients [35,57–62].
Aerosolized magnesium (0.66 g in 10 mL of saline) and intravenous magnesium
solutions (1.2 g over 20 minutes) have been used investigationally to treat pa-
tients who have asthma for whom maximal standard therapy has failed, although
neither form is approved for this indication in the United States. Bronchodilation
is observed within 2 to 5 minutes after administration, but it disappears rapidly
after treatment is discontinued; therefore, additional bronchodilator therapy must
accompany the use of magnesium. Side effects include hypotension, malaise, and
a warm sensation. Cardiac rhythm, blood pressure, pulse, neurologic status, and
renal function must be monitored closely.
Heliox. Heliox, an 80:20 mixture of helium and oxygen, sometimes is con-

sidered for treatment in patients who have respiratory acidosis and who fail
conventional therapy. Helium is a low-density, biologically inert gas that lowers
airway resistance and decreases respiratory work. Significant improvement may
be noted within 10 to 20 minutes of initiating therapy, but there are insufficient
data on whether heliox can avert tracheal intubation, change intensive care and
hospital admission rates and duration, or affect mortality [63,64]. One case report
described the use of heliox in a pregnant, intubated asthmatic [65,66], but other-
wise, the use of heliox has not been studied in pregnancy.
Assisted ventilation. Noninvasive respiratory therapies, such as continuous

positive airway pressure and biphasic positive airway pressure, have been shown
to reduce the work of breathing and to improve oxygenation for some causes of
respiratory failure. More data are needed to support this intervention in acute
asthma exacerbation [51,65,66].
If the patient’s condition deteriorates or fails to improve despite intensive
therapy, the use of intubation and mechanical ventilation must be considered.
Although there are no absolute criteria other than respiratory arrest and coma,
patients who have the following symptoms should be considered for intubation
and mechanical ventilation: worsening pulmonary function tests, despite vigorous
bronchodilator therapy; decreasing Pao2, increasing Paco2, or progressive
respiratory acidosis; declining mental status; and increasing fatigue.
Randomized controlled trials to evaluate methods of ventilation during
treatment of severe, life-threatening acute asthma are lacking. Because airflow
obstruction can result in air trapping and higher lung volumes in mechanically
ventilated asthmatics, it is suggested that asthmatics who require intubation be
ventilated using ‘‘permissive hypercapnia.’’ This technique usually avoids the
development of auto-PEEP (positive end-expiratory pressure) by using a rapid
inspiratory flow rate, a reduced respiratory frequency, and a prolonged expiratory
phase [67,68]. Should auto-PEEP develop and result in a continuously increased
intrathoracic pressure that may decrease venous return and cause hypotension, it
can be treated by disconnecting the patient from the ventilator and allowing the
lungs to deflate completely before reconnecting.
Disposition decisions
All patients should be observed and re-evaluated frequently during and after
treatment. The disposition decision should be based on duration, course, and
severity of symptoms; severity of airflow obstruction; course and severity of
previous exacerbations; medication use at the time of the exacerbation; access
to medical care and medications; and adequacy of support and home conditions
(see Fig. 2). If in doubt, it is advisable to err on the side of caution and observe
the patient longer in the emergency department, observation unit, or hospital.
Although there are no reliable criteria to predict who will be discharged suc-
cessfully and who will relapse [21,69–73], careful discharge planning may help
to avoid future problems.
Patients should be provided with a schedule for ongoing short-acting b-2
agonist use and a 3- to 10-day burst of oral corticosteroids [74]. Data indicate that
emergency physicians are less likely to prescribe systemic corticosteroids to
pregnant asthmatic women who experience exacerbation than to nonpregnant
asthmatic women, and that pregnant asthmatic women are three times more likely
to report ongoing exacerbation at 2 weeks after emergency department dis-
charge [21].
Patients who are on ICSs should be advised to continue their use, whereas
asthmatics who have persistent disease and who are not already on ICSs should
be advised to begin taking them. One observational study suggested that inhaled
steroids prevented asthma exacerbations during pregnancy [9]. In addition, a
randomized controlled trial showed that discharge on ICSs, in addition to oral
steroids and b-2 agonists, reduced repeat asthma exacerbations in pregnant
women who were hospitalized for asthma [75]. Finally, patient education, a
personalized action plan for worsening of symptoms, and advice for close follow-
up should be provided.
Summary
In addition to preventing maternal and fetal hypoxia, the goals of treating

acute asthma exacerbation during pregnancy mirror those in the nongravid
patient: rapid reversal of airflow obstruction with aerosolized bronchodilators,
reduction of likelihood of recurrence by the addition of corticosteroids, and
ongoing assessment of mother and fetus. Disposition decisions are multifaceted
and must take into account the health and well-being of the pregnant patient and
that of her fetus. Discharge planning includes prescription of scheduled b-2
114 cydulka
agonist treatments until symptoms resolve, intensification of daily treatment as

needed, prescriptions for systemic and ICSs, as well provision of patient
education, a personalized action plan, and close follow-up.
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26 (2006) 119 – 135
Pregnancy Rhinitis
Eva K. Elleg3rd, MD, PhD
Department of Otorhinolaryngology, Kungsbacka Hospital, S-434 80 Kungsbacka, Sweden
Pregnancy rhinitis has evolved only lately as a defined condition to be taken

seriously, even though nasal congestion that is due to pregnancy has been known
as a phenomenon for years. It may seem to be a harmless condition compared
with, for example, preeclampsia, which is considered ‘‘the commonest cause of
maternal and fetal morbidity and mortality,’’ and occurs in 7% to 9% of the
pregnant population [1]. There is a possible connection between pregnancy
rhinitis and preeclampsia, which makes the subject even more important to study.
This possible connection is snoring. Snoring is common during pregnancy,
and may have negative effects, such as maternal hypertension, preeclampsia,
intrauterine growth retardation, and lower Apgar scores [2]. It is well known
that nasal congestion increases when the subject is in the supine position,
especially in patients who suffer from rhinitis [3], and that nasal congestion may
result in snoring.
Air passing in through the nose is prepared to suit the lungs; it is filtered from
particles, tempered, and humidified. Nasally inhaled air also transports nitric oxide
(NO) from the sinonasal unit to the lungs and gives vasodilatation [4]. Nasal
congestion may force the subject into mouth breathing, which lacks these
functions. Mouth breathing also gives a dry mouth, and with less saliva, the dental
protection system against caries is disturbed. Long-standing nasal congestion also
can predispose to sinusitis.
Quality of life scores are worse in allergic rhinitis than in asthma, and possibly
are influenced by problems like daytime tiredness, thirst, poor concentration, and
headache [5]. A parallel to the symptoms of pregnancy rhinitis seems obvious,
but this has not been evaluated.
Rhinitis medicamentosa has become recognized as a problem during the last
decades. Women who have pregnancy rhinitis tend to overuse nasal deconges-
E-mail addresses: eva.ellegard@lthalland.se, eva.ellegard@gmail.com
120 ellegård
tants, and to develop an additional rhinitis medicamentosa, which does not

resolve spontaneously after delivery [6].
Knowledge of nasal congestion, such as outlined above, probably is confined to
ear, nose and throat– and allergy-oriented physicians, whereas pregnant women
are mainly in contact with their obstetricians, who may not be aware of the
problem.. Research and education should increase the knowledge of this problem
by health care professionals and patients, and lead to improved management and
quality of life. .
Historical knowledge
In the late nineteenth century, several scientific papers reported observations

that connected the female genitals with the nose. A case report from 1881 [7]
described a woman who had ozena, which worsened during menstruation. In 1884,
Mac Kenzie [8] quoted the Ayurvéda, Hippocrates and Celsus, and several
nineteenth century writers, and presented multiple observations of his own on ‘‘the
erection of the nasal turbinated structures’’ during menstruation, and worsening of
nasal symptoms during menstruation or sexual excitement. Expanding his theories,
he included nasal congestion during pregnancy in 1898 [9]. In 1892, Endriss [10]
described epistaxis and worsening of nasal disease that was due to menstruation.
After this period, the interest seems to have faded until 1943, when Mohun
[11] presented 20 cases of ’’vasomotor rhinitis’’ during pregnancy. Nasal symp-
toms in these patients appeared in the third to seventh month of gestation,
persisted to term, and normalized in all but one patient within 10 days post
partum. He concluded that there was a connection with estrogen, but also that
‘‘the acromegaly of pregnancy may in some way predispose the nasal structure to
vasomotor rhinitis.’’
Estrogen was assumed to influence the nasal mucosa, and there were case
reports of successful nasal estrogen treatment of atrophic rhinitis [12,13]. Holmes
and colleagues [14] stated in 1950, that ‘‘the occurrence of hyperemia with
swelling and hypersecretion in the nose as an accompaniment of menstruation
does not require further confirmation.’’ They emphasized the influence of psy-
chologic factors on the pathogenesis of those symptoms in menstruation as well
as in pregnancy.
Possible influence of rhinitis on the fetus
It is well known that nasal congestion increases when the subject is in the
supine position, especially in patients who suffer from rhinitis [3]. Difficulty
breathing through the nose increases the tendency to revert to mouth breathing,
and snoring. Regular snoring, reported in 9% out of 73,231 nonpregnant women,
was associated with hypertension independent of body mass index [15]. In a
questionnaire study in 502 women the day after delivery, habitual snoring the
pregnancy rhinitis 121
previous week was reported in 23% [2]. Snorers had a significantly higher fre-
quency of hypertension, preeclampsia, and intrauterine growth retardation, and
the Apgar scores of their babies were lower.
Inhaled NO is produced mainly in the maxillary sinuses. It reduces pulmonary
vascular resistance and increases pulmonary oxygenation [16]. Mouth breathing
that is due to pregnancy rhinitis may reduce this inhalation, affect pulmonary
vascular tone or oxygenation, and thus, affect the oxygen supply to the fetus. This
could be a mechanism of the complications that are associated with snoring that
were described above.
Furthermore, there is a risk that pregnancy rhinitis induces obstructive sleep
apnea in women who are predisposed to that disease, but who normally can
breathe through the nose. Hypertension that is associated with preeclampsia is
characterized by an increase in nocturnal blood pressure, a pattern that was
reported to be associated with snoring and obstructive sleep apnea [1].
Definition for research purposes
Many investigators have studied the nasal congestion of pregnant women

without a proper definition of the phenomenon. Some have described it as a
condition that appears at the end of the first trimester and disappears after
delivery [17,18]. Another study found that unspecified subjective nasal con-
gestion was increased significantly only during the third trimester compared with
nonpregnant subjects [19].
With the aim to define pregnancy rhinitis, we followed 23 women, who scored
nasal congestion and registered nasal peak expiratory flow (nPEF) daily until
1 month after delivery [20]. The women were more congested during pregnancy,
than after pregnancy, excluding days with other signs of respiratory tract infection
Fig. 1. Subjective nasal congestion scores (0–4) of 23 women during three 4-week periods. Scores
in gestational weeks 15–18 (early), and in the last month preceding delivery (late) were significantly
higher than in the month after delivery (after) ( P = .001, Wilcoxon signed rank test). (From Elleg3rd
E. Clinical and pathogenetic characteristics of pregnancy rhinitis. Clin Rev Allergy Immunol 2004;
26:149–59; with permission.)
122 ellegård
(Fig. 1). In cases where, by our clinical experience, we were convinced that there
was nasal congestion caused by pregnancy, we made the diagnosis. We then
looked at the cases, and identified the criteria that would separate them from the
rest of the women. This resulted in our clinical definition ‘‘nasal congestion
present during the last 6 or more weeks of pregnancy without other signs of
respiratory tract infection and with no known allergic cause, disappearing com-
pletely within 2 weeks after delivery.’’ These diagnostic criteria for pregnancy
rhinitis include the natural course after delivery, to make studies on etiology and
epidemiology possible.
Nasal mucociliary transport speed was not affected in the group of women
who had pregnancy rhinitis; however, it was decreased significantly during
pregnancy in the group of women who did not have the condition [21]. A similar
[22], and a reverse [23] physiologic change have been reported, which suggests
that further research is needed.
Diagnosis
The clinical diagnosis of pregnancy rhinitis can be made once a pregnant

woman who has nasal congestion that is not due to any other condition presents
for care. In addition to congestion, patients often suffer from watery or viscous
clear secretion from the nose. The swollen mucosa of the nasal turbinates
responds to local decongestion, which makes complete inspection of the nasal
cavities possible (Fig. 2). Objective measurements of nasal congestion can be
used in scientific studies, but are not needed for the clinical diagnosis. Mea-
surement of mucociliary transport speed is of no diagnostic value.
Differential diagnosis
Rhinitis medicamentosa is a differential diagnosis (Box 1) as well as a com-

plication to pregnancy rhinitis, because nasal decongestants give good temporary
relief. Most patients do not mention their long-standing use of nasal deconges-
tants spontaneously, and it is important to question them about it. In nonpregnant
persons who have rhinitis medicamentosa, the rebound congestion usually disap-
pears within 2 days after the use of nasal decongestants has stopped [24]. In
pregnancy, clinical experience suggests it more commonly takes 1 week to resolve.
Sinusitis (see the article elsewhere in this issue) may be a differential diagnosis
and a complication of pregnancy rhinitis. Even in nonpregnant patients, sinusitis
often is a difficult diagnosis to make, and the presence of nasal congestion lacks
specificity in that respect. Pus in the middle meatus, sensation of foul smell,
unilateral predominance of purulent secretion, and unilateral predominance of
local pain have been suggested as strong diagnostic signs for sinusitis [25], but
these signs are more specific than sensitive [26]. Furthermore, in pregnancy, nasal
congestion may be the only symptom of sinusitis [27]. Decongestion facilitates
Fig. 2. Endoscopic appearance of the right inferior turbinate in pregnancy rhinitis before (top)
and after (bottom) decongestion. (From: Elleg3rd E. Clinical and pathogenetic characteristics of
pregnancy rhinitis. Clin Rev Allergy Immunol 2004;26:149–59; with permission.)
nose inspection, which is best performed with an endoscope, but anterior

rhinoscopy also is useful. Ultrasound examination of the sinuses can be an
additional tool in experienced hands. In exceptional cases, a radiograph may be
needed, taking care not to expose the fetus. Antral puncture is the ultimate
diagnostic method for sinus empyema.
Box 1. Differential diagnosis
Rhinitis medicamentosa
Sinusitis
Upper respiratory tract infection
Airborne allergy
Nasal granuloma gravidarum
124 ellegård
Upper respiratory tract infection other than sinusitis is more obviously in-
fective, is not confined to nasal congestion, and is not as long-standing.
Airborne allergy is another common differential diagnosis. Nasal congestion
in patients who have allergic rhinitis is accompanied most often by excessive
watery secretion, and sneezing, which is not the case in pregnancy rhinitis.
Allergic rhinitis that is due to house dust mites, however, frequently presents with
nasal congestion as the most prominent symptom. If it appears during pregnancy
for the first time, it is difficult to differentiate from pregnancy rhinitis, and the
two conditions may coexist. Relevant in vitro blood tests for specific IgE ex-
cludes allergy.
Nasal granuloma gravidarum (also known as pregnancy tumor, pregnancy
granuloma, telangiectatic polyp) is a rapidly growing benign tumor that causes
nasal obstruction. The histology is nearly the same as in pyogenic granuloma. In
contrast to pregnancy rhinitis, it almost always is unilateral, and it tends to cause
recurrent nosebleed. Inspection of the nasal cavity reveals a well-vascularized
lesion that bleeds easily upon touch. It even may protrude and occupy the nasal
vestibulum and be seen readily from the outside. If nasal obstruction or nose-
bleeds are troublesome, excision under local anesthesia is indicated, but it may
disappear completely by itself after delivery [28].
Etiology
Nasal mucosal swelling can be caused by increased vascular pooling of blood

that is caused by a decrease in a-adrenergic tone in the venous sinusoids, or by
edema that is caused by leakage of plasma from the vascular bed into the stroma.
No hormone is known to activate any of these pathways in the nasal mucosa.
Estrogen
The theory that estrogen causes nasal congestion mainly is based scientifically
on the results of Toppozada and colleagues [18] from biopsy studies on nasal
mucosa in pregnancy, and from women who were taking contraceptive pills [29],
although a similar study during the menstrual cycle failed to show any cyclic
changes [30]. Nasal congestion was a known side effect of the early high-
estrogen contraceptive pills.
If estrogen causes nasal congestion, this should be found during the pre-
ovulatory and luteal phases of the menstrual cycle, when the serum levels of
estrogen are highest. In a study over several months on 41 normally menstruating
women, significantly more congestion was found during the menstrual phase,
when the estrogen levels are lowest [31]. Furthermore, serum levels of estradiol
that were measured four times during pregnancy in 23 women were not higher in
women who had pregnancy rhinitis [32]. Moreover, recent studies on
postmenopausal women suggest that estrogen replacement therapy may reduce
subjective nasal congestion [37].
If estrogen causes nasal congestion, one would expect increasing congestion

in every pregnant woman. In 23 pregnant women, only 8 had increasing con-
gestion, and 9 individuals registered declining congestion in the course of preg-
nancy [20]. A similar pattern was seen in a recent study, although the mean
results of different measurements indicated increasing congestion during preg-
nancy [23]. A parallel is obvious: about one third of asthmatics improve during
pregnancy, whereas one third deteriorate [33]. Although reports of the exact
proportions vary, the existence of this variation in pregnant asthmatics seems to
be indisputable [34].
A study on 568 patients also showed a significant relationship between the self-
reported change in asthma course during pregnancy, and that of rhinitis [35]. This
agrees with the well-known concept of the ‘‘united airways’’ in nonpregnant pa-
tients, where upper and lower airway inflammatory events influence each other,
because they are part of a systemic condition with variable manifestations [36].
Progesterone
Increased circulating blood volume, possibly enhanced by a vasodilating effect

of progesterone, was suggested as being responsible for pregnancy-induced nasal
congestion [38]. Serum levels of progesterone were similar in groups of women who
did and did not have pregnancy rhinitis, which does not support this theory [32].
Prolactin
The pituitary increases production of prolactin during pregnancy, which

suggests a possible role in the pathogenesis of pregnancy rhinitis; however, this is
contradicted by the absence of sinus pathology in patients who have prolactinoma
[39]. Furthermore, bromocriptine and quinagolide, which reduce prolactin, have
nasal congestion as known side effects.
Neuropeptides
Vasoactive intestinal polypeptide (VIP) is associated with other sorts of rhi-

nitis [40], and has been proposed as a possible mediator of the vasodilation in the
nasal mucosa that is responsible for nasal congestion during pregnancy. A study
on serum levels did not support this theory [41].
Nasal biopsies of postmenopausal women showed increased immunopositivity
for estradiol, estradiol receptor, VIP, and substance P (SP) after 6 months of
hormone replacement therapy. There was a reduction in neuropeptide Y (NPY).
Nasal application induced stronger changes than did transdermal application
of hormone replacement therapy. Mucociliary transport time and subjective
nasal congestion decreased, but anterior rhinomanometry was unchanged. The
investigators proposed that estrogen action in the nasal mucosa is mediated by
neuropeptides—an increase of gland secretion and vasodilatation by VIP and SP,
and a decrease of NPY-induced vasoconstriction [37]. Other than the one study
126 ellegård
that was mentioned above [41], neuropeptides have not been evaluated in patients
who have pregnancy rhinitis.
Placental growth hormone
After the first trimester of pregnancy, the episodic bursts of human growth
hormone (hGH) are replaced by a continuous secretion with increasing values of
a placental growth hormone variant (PGH) [42]. In our study, serum levels of
PGH were significantly higher in the group that pregnancy rhinitis on all occa-
sions throughout pregnancy [32].
In acromegaly, the possibility of a ‘‘hormonal rhinitis’’ has been suggested
[43]. A study by Skinner and Richards [39] supports this theory: that hGH may
induce changes in the mucosa of the upper airways. In their study, patients who
had acromegaly had an increased frequency of mucosal hypertrophy and polyps
in the sinuses compared with patients who had prolactinoma. No such pathology
was found in the nasal mucosa, however, which was examined after preoperative
cocaine treatment. It is possible that PGH may stimulate mucosal growth in a
similar way, and thereby, induce pregnancy rhinitis. If PGH were the single cause
of pregnancy rhinitis, it would be expected to occur in all pregnant women.
Further studies will be necessary to determine the etiology of pregnancy rhinitis.
Incidence
Earlier incidence figures were based on small numbers of women: 30% in

79 women [17], 18% in 66 women [44], and 21% in 160 women [45]. In a
questionnaire study, of 810 women who were asked about subjective nasal
congestion upon all visits to the midwife during and after pregnancy, pregnancy
rhinitis was present in 22% of the 599 women who completed the study [46].
Nasal congestion manifested itself in gestational weeks 7 through 36 (ie, from as
early as it was possible to register, until as late as possible to obtain a 6-week
duration; Fig. 3). The incidence of pregnancy rhinitis may have been under-
estimated, because women who had long-standing nasal problems before
conception were excluded. But because their symptoms may have varied over
time in the nonpregnant state, it was too difficult to evaluate what impact
pregnancy may have had.
In another Swedish study, 2264 pregnant women were asked whether they had
had ‘‘daily nasal stuffiness during the last 3 weeks’’ on visits in gestational weeks
12, 20, 30, and 36. Women with any positive answer made up the ‘‘stuffiness’’
group, which then included all sorts of rhinitis. The ‘‘stuffiness’’ rate was 42% in
week 36 of gestation. Out of 1546 women who answered on all four occasions,
11% reported ‘‘stuffiness’’ every time [47].
One study failed to show any significantly increased frequency of nasal
congestion during pregnancy [48]. The investigators asked 27 nonpregnant
women and 33 pregnant women once in each trimester to score nasal congestion
Fig. 3. Debut of nasal congestion due to pregnancy rhinitis in 133 women. (From: Elleg3rd E,
Hellgren M, Torén K, et al. The incidence of pregnancy rhinitis. Gynecol Obstet Invest 2000;49:
98–101; with permission.)
on a visual analog scale and compared the ‘‘prevalence of congestion.’’ The cut-
off level that was used to define congestion was not specified in the article. The
resulting 33% (nonpregnant), 61% (first trimester), 55% (second trimester), and
55% (third trimester) were not reported to be significantly different (despite that
‘‘congestion’’ in pregnancy was almost twice as frequent as in the controls). Their
method is unlikely to be appropriate for such a small number of women, but no
power calculation was presented.
Risk factors
Smoking
The incidence of pregnancy rhinitis in our questionnaire study was signifi-

cantly higher in smokers than in nonsmokers (odds ratio, 1.7; 95% confidence
interval; 1.1–2.5) [49]. It is possible that the irritating effects of smoking are
additive to other changes that induce nasal congestion.
Allergy
Toppozada and colleagues [18] reported that the electron microscopic findings
from nasal mucosa from pregnant women who had nasal symptoms were
identical to those in allergic rhinitis. Mabry [44] found no connection between
anamnestically constant or frequent nasal congestion in pregnancy, and pre-
viously documented allergic rhinitis.
Asthma, hay fever, and month of conception were not associated with
pregnancy rhinitis in our questionnaire study [46]. We performed in vitro tests for
10 common airborne allergens on 165 of those women, 83 of whom had had
128 ellegård
pregnancy rhinitis [49]. The overall sensitization rate was not increased in the
group of women who had had pregnancy rhinitis; however, sensitization to house
dust mites was more frequent in that group. Thus, the few women who have high
levels of IgE against house dust mites seem predisposed to get pregnancy rhinitis.
It was impossible to differentiate their rhinitis from a subclinical allergic rhinitis
with deterioration during pregnancy, but it was remarkable that they all recovered
after delivery.
Serum levels of soluble intercellular adhesion molecule–1 (sICAM-1) are
elevated in perennial [50], and seasonal allergic rhinitis [51], and can be used as a
marker of allergic nasal disease. In our study of 23 pregnant women, the mean
serum values of sICAM-1 did not change significantly over time, and the group
of women who had pregnancy rhinitis had similar values as did the group that did
not have the diagnosis [49].
Nasal hyperreactivity
To differentiate subjects who have nasal hyperreactvitiy from controls using

rhinostereometry, a limit of 0.4 mm ipsilateral congestion 5 minutes after provo-
cation with histamine 2 mg/mL has been proposed [52]. We evaluated nasal
hyperreactivity that was determined in this way in 12 women who had had
pregnancy rhinitis and 13 women who had not had pregnancy rhinitis [49]. There
was no difference between the two groups. In addition, there were no differences
between the groups regarding reactions to increasing concentrations of histamine,
as measured by rhinostereometry or acoustic rhinometry.
Treatment
Antenatal care information
Women who know that pregnancy can induce nasal congestion and are in-
formed of the treatment options presumably handle it better if it appears. Patients
are less likely to be worried if they know that their nasal congestion is a common,
self-limiting experience, which they share with generations of women. As
Rambur [53] suggested, information on pregnancy rhinitis should be given to all
pregnant women on their first antenatal care visit (Box 2). This requires an
educational effort that is directed toward the antenatal staff as well.
Physiologic measures
Physical exercise has a well-known decongesting effect on the nasal mucosa

[54]. The normal fatigue and well being that follow exercise also may have an
additional positive effect on sleep disturbance that is caused by nasal congestion.
‘‘Raise the head end of the bed when your nose is congested’’—most patients
have heard this simple advice but they may need to be reminded of it. The
Box 2. Treatment considerations
General
Information to all pregnant women

Physical exercise
Raised head end of bed
Mechanical nasal alar dilation
Nasal saline washings
Special indications
Nasal decongestants
Nasal corticosteroids
Nasal continuous positive airway pressure
Invasive inferior turbinate reduction
Not indicated
Systemic corticosteroids
Oral decongestants
Antibiotics
effective angle is 308 [3] or 458 [55]. It is easier to tolerate ‘‘books under the legs
of the head end of the bed’’ than extra pillows, when the side position is desired.
In pregnancy, that position is favorable because of the vena cava syndrome, and
because it reduces the risk of snoring.
Different mechanical devices are available to dilate the nasal valve region,
which is the narrowest part of the airway. An external type of device improved
subjective nasal breathing in patients who had ‘‘pregnancy-related nocturnal
nasal congestion’’ [45]. An internal type of device reduced snoring significantly
in men [56], and was as effective as a nasal decongestant in healthy subjects [57].
Because the possible problems that are associated with the use of these devices
are limited to local irritation of the skin by glue or pressure, they are well worth
trying, especially when nasal congestion disturbs sleep. Nasal valve muscular
training [58] might prove to be another effective way to improve nasal breathing.
Nasal saline washings
In the author’s clinical experience, nasal washings with physiologic saline

solution (5 mL of salt in 0.5 L of water) are effective in reducing symptoms for
many women who have pregnancy rhinitis; they also work well for other sorts
of rhinitis. The patient prepares the solution at home, and leans forward when
130 ellegård
taking it through her nose. She can sniff it in from her cupped hand, or she can
use any of the products that are available to make the administration more
comfortable. There are no restrictions on how often it may be used. The saline
gives temporary relief, reduces the amount of secretions, and removes crusts that
impair the nasal airway.
Nasal decongestants
Nasal decongestants give good temporary relief in pregnancy rhinitis. But

because the condition does not resolve in a few days, like a common cold does,
pregnant women who have nasal symptoms tend to use them for prolonged
periods of time. This results in the additional condition of rhinitis medicamen-
tosa, which does not resolve spontaneously after delivery. Rebound swelling of
the mucosa increases nasal congestion when the decongestive effect of the drug
has disappeared. To alleviate this symptom, patients gradually use larger doses
of the vasoconstrictor more frequently. The preservative, benzalkonium chloride,
in the nasal preparation worsens the congestion [59]. Many patients are unaware
of the condition. They get used to the decongested state as being normal, and they
need to be informed about the situation [6]. Even a dosage that was given only in
the evenings to healthy subjects resulted in rhinitis medicamentosa [60]. Some
investigators recommend that during pregnancy, nasal decongestants should not
be used for more than 5 days [38] or even 3 days [61]. It is possible that lower
concentrations and unilateral, alternating nostril administration may be used
safely only in the evening for longer periods of time, but this needs to be studied.
Oral decongestants
Orally administered vasoconstrictors, such as phenylpropanolamine and pseu-

doephedrine, are used widely in various sorts of rhinitis [62]. No data are
available on whether they are effective in pregnancy rhinitis. The recommenda-
tions for their use during pregnancy vary between countries. For example,
phenylpropanolamine is the oral decongestant that is classified to be safe for use
during pregnancy in Sweden, whereas pseudoephedrine is preferred in U.S.
guidelines [62]. Earlier reports indicated an increased risk for the malformation
gastroschisis, but this could not be confirmed in a larger study on 206 cases and
798 controls [63]. It seems unwise to risk the general systemic adverse effects of
oral decongestants, which may include elevated blood pressure, palpitations, loss
of appetite, tremor, and sleep disturbance.
Nasal corticosteroids
Nasal corticosteroids are effective in allergic rhinitis [64,65]; rhinitis medi-

camentosa [66]; perennial, nonallergic rhinitis [67]; and nasal polyps [68]. It is
important to inform the patient that the anticipated effect is not as immediate and
obvious as that of nasal decongestants. Pregnant patients were not included in any
of these studies, and the documentation of treatment during pregnancy is limited.
Fluticasone propionate nasal spray did not show any effect on pregnancy
rhinitis in 53 women treated for 8 weeks in a placebo-controlled, randomized,
double-blind study with parallel groups, as evaluated by daily symptom scores,
nPEF, and acoustic rhinometry [69]. There also were no detectable influences on
maternal morning S-cortisol and overnight 12-h-U-cortisol, nor any difference in
ultrasound measures of fetal growth, or pregnancy outcome.
Budesonide that was inhaled for asthma by women in early pregnancy did not
increase the rate of congenital malformations in 2014 infants compared with the
general population rate, according to figures from the Swedish Medical Birth
Registry [70]. Thus, it probably also could be used safely in this respect when
inhaled nasally for rhinitis during pregnancy. Published data show that the
currently available inhaled steroids used at clinically relevant doses do not impair
intrauterine growth [71].
Systemic corticosteroids
Corticosteroids have been administered systemically for various nasal con-

ditions, but prolonged or repeated use should be avoided to prevent adrenal
suppression, and other systemic side effects. Mabry [17] described his experience
in treating congested nasal mucosa in pregnancy. In his opinion, up to 2 weeks’
duration of oral corticosteroids may give temporary relief and allow the with-
drawal of nasal decongestants, and intranasal submucosal injections of cortico-
steroids produced improvement within a few hours that lasted for 4 to 6 weeks.
No rigorous clinical studies have been published on the safety or efficacy of these
treatments during pregnancy, and the side effects from intranasal steroid in-
jections include blindness.
Antibiotics
Pregnancy rhinitis is not an indication for treatment with antibiotics; however,

sinusitis during pregnancy should be treated with an elevated dosage of anti-
biotics (see elsewhere in this issue). Because of increased renal clearance, the
dosage of betalactam antibiotics needs to be increased by 50% [72]. An extra
dose per day is recommended, to increase the time over ‘‘minimum inhibitory
concentration.’’ Repeated antral irrigations may be needed when the sinusitis has
been long-standing. This is facilitated by the use of a narrow catheter, which is
left at the puncture site for a few days (eg, SinoJect).
Nasal continuous positive airway pressure
Nasal continuous positive airway pressure (CPAP) is not indicated in isolated

pregnancy rhinitis, but it can be considered in cases of obstructive sleep apnea.
As in nonpregnant patients, nasal CPAP has been used with excellent compliance
132 ellegård
for that diagnosis, and was shown to be effective as measured by polysomnog-

raphy. Readjustment of the CPAP pressure may be needed during the course of
pregnancy [73].
In a noteworthy study, although not randomized, nasal CPAP reduced
nocturnal blood pressure significantly in women who had preeclampsia, although
they did not have obstructive sleep apnea [1].
Surgery
Noninvasive methods, such as electrocautery, cryotherapy, laser, or radio-

frequency, can be used to reduce mucosal swelling of the inferior turbinates in
pregnancy rhinitis [53]. Each method has its advantages, as have different types
of surgical reduction. The effect may be temporary or permanent, and the fre-
quency, degree, and persistence of side effects (eg, crusting, edema, bleeding)
varies [74]. The spontaneous healing of pregnancy rhinitis after delivery must be
kept in mind. These methods should be considered carefully in desperate cases
only (eg, if other sorts of treatment of the nose fail and CPAP is not tolerated in a
woman who has pregnancy rhinitis and obstructive sleep apnea).
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26 (2006) 137 – 154
The Diagnosis and Treatment of Allergic

Rhinitis During Pregnancy and Lactation
Gary A. Incaudo, MDa,b,T, Patricia Takach, MDa,b
a
Department of Internal Medicine, University of California, Davis School of Medicine, 4150 V Street,
#3100, Davis, CA 95817, USA
b
Allergy Associates, 145 Mission Ranch Boulevard, Suite 110, Chico, CA 95926, USA
Upper airway congestive symptoms during pregnancy have been recognized

since the late nineteenth century [1]. Among randomly selected pregnancies, as
many as 18% to 30% of patients report substantial symptoms of rhinitis and
sinusitis; this percentage may be higher among patients who have pre-existing
atopic disease [2–4]. Nasal conditions during pregnancy can take many forms.
For example, hormone surges in pregnancy can induce a form of rhinitis, termed
‘‘rhinitis of pregnancy,’’ which presents as congestion (see elsewhere in this
volume). This congestion often is difficult to distinguish from other forms of
rhinitis that may be present during pregnancy. Furthermore, coexisting and mild
forms of rhinitis may be amplified or uncovered by the physiologic changes that
are characteristic of pregnancy. Comorbid features of allergic rhinitis during
pregnancy, such as sinus disease, asthma exacerbation, and sleep interference, are
common because of the understandable reluctance of mothers to undergo diag-
nostic or therapeutic intervention for something that ‘‘can wait’’ until the preg-
nancy is completed.
Twenty to forty percent of women in their childbearing years have some form
of allergy [5]. Of those pregnant women who have known allergies, some studies
suggest that as many as 10% to 30% experience increasing allergic symptoms
during their pregnancy and return to their normal prepregnancy state after deliv-
ery [5–7]. In addition, increased circulating blood volume and hormonal in-
fluences on nasal mucosal secretions that are seen in pregnancy promote nasal
* Corresponding author. Department of Internal Medicine, University of California, Davis School

of Medicine, 4150 V Street, #3100, Davis, CA 95817.
E-mail address: gaincaudo@ucdavis.edu (G.A. Incaudo).
138 incaudo & takach
vascular engorgement and noticeable nasal congestion [8,9]. It stands to reason,

therefore, that pregnancy can amplify any pre-existing nasal condition.
There are limited data regarding the clinical effects of the various forms of
rhinitis on pregnancy outcomes. On the surface, it seems unlikely that gestational
rhinitis alone would have a deleterious effect on the course of pregnancy; how-
ever, uncontrolled allergic rhinitis or sinusitis during pregnancy may aggravate
coexisting asthma, and cause a distinct, adverse effect on pregnancy outcome.
Furthermore, nasal obstruction may affect the pregnant mother’s eating, sleep-
ing, and emotional well being, which indirectly could affect pregnancy adversely.
For example, rhinitis during pregnancy may cause snoring, which has been asso-
ciated with pregnancy-induced hypertension and intrauterine growth retarda-
tion [10]. To optimize pregnancy outcome, the health care provider should be
knowledgeable about rhinitis during pregnancy, become familiar with potential
comorbidities, and use specialists to optimize pregnancy outcome when compli-
cations emerge.
The differential diagnosis of nasal symptoms during pregnancy
Nasal pathologies during pregnancy are a compendium of nasal and sinus

problems that are typical of that age group, which are enhanced by some of the
physiologic changes that are unique to pregnancy. Prominent in the differential
diagnosis of nasal symptoms during pregnancy are viral infection or bacterial
sinusitis following viral infection, allergic rhinitis, rhinitis medicamentosa, nasal
septal or turbinate deformities, nasal polyps, and the ‘‘rhinitis of pregnancy.’’
Each of these conditions may exist by itself, occur in various combinations, or
emerge to greater prominence because of the hormonal influences on the nasal
mucosa and nasal secretions. For example, infectious sinusitis seems to be in-
creased in pregnancy and reportedly complicated as many as 1.5% of preg-
nancies, a sixfold increase over the frequency that was observed in a nonpregnant
population [9]. Pregnant women also may abuse topical nasal decongestants
(rhinitis medicamentosa) when relief is required for chronic congestion, likely
because of their inclination to favor topical medications over oral medications
to protect their fetus [11].
Viral infections
There are no data to suggest that upper respiratory viral infections occur more
frequently in pregnant women; however, such viral infections are common and
induce direct tissue damage to the nasal mucosa. Some indirect consequences of
viral invasion are nasal mucosa hyperactivity and impaired nasal mucociliary
clearance. Secondary bacterial invasion is enhanced in these circumstances, es-
pecially from the heavily colonized nasal cavity to the sterile paranasal sinuses.
Any coexisting nasal conditions, including the physiologic hormonal effects on
allergic rhinitis during pregnancy & lactation 139
the nasal mucosa during pregnancy, complicate the picture and enhance the
probability that bacterial sinus disease will evolve. As allergists, we often see
women who have chronic sinus disease—the origin of which seems to be related
to pregnancy—and who were reluctant to seek intervention.
Atopy
The peak age of child bearing corresponds with the peak age of onset of
allergic disease. Foxen and colleagues [12] suggested that nasal allergy can
be exacerbated or initiated by pregnancy. Other investigators have refuted this
impression, and used the fact that there is no consistent change in serum IgE
during pregnancy as evidence [13]. At the very least, pregnancy tends to occur
during a period in a woman’s life that coincides with the peak age of onset or
expression of allergic rhinitis. Furthermore, the physiologic effects of pregnancy
on the respiratory tract can influence the clinical expression of any IgE-mediated
response. One report found that during pregnancy, nasal symptoms in patients
who had known allergic rhinitis improved in 34%, worsened in 15%, and re-
mained unchanged in 51% [5].
Anatomic obstruction
Anatomic variations, such as septal deflections, polyps, and turbinate hyper-

trophy (primary or secondary due to allergies or rhinitis medicamentosa), can
influence nasal obstruction. The degree of obstruction varies according to the
extent and location of the anatomic blockage. The pregnant patient who com-
plains of nasal congestion always should be questioned about the use of topical
nasal decongestants. Turbinate hypertrophy that is not related to topical de-
congestant abuse and nasal polyps generally represent the end-product of more
severe pre-existing nasal disease, and suggest the need for a thorough inves-
tigation following delivery.
Sinusitis
The actual extent and mechanisms that are responsible for the increased
incidence of bacterial respiratory infections during pregnancy remain uncertain.
There is alteration of maternal cell–mediated immunity during pregnancy, but
this seems to be a selective process that does not cause a predisposition to in-
fections [12,14]. Furthermore, most of the available evidence supports normal
functioning of humoral maternal immunity during gestation [15]. There are no
data to support the notion that the immunologic changes that occur during preg-
nancy explain the observed increased incidence of purulent sinusitis.
Limited clinical observations have been made concerning bacterial sinusitis in
pregnancy. The organisms seem to be the typical Streptococcus pneumonae,
Haemophilus influenzae, and Moraxella catarrhalis, with the peak onset in the
second trimester. Of concern to the medical practitioner is that classic symptoms
and signs of sinusitis are absent in nearly half of the women who have docu-
mented purulent sinusitis during pregnancy [9]. Even in the nonpregnant state,
sinusitis can be notoriously subtle in its clinical presentation, with little in the
patient history or physical findings to support a firm diagnosis. Considering
the sixfold increased frequency of sinusitis in pregnancy, health care providers
should maintain a high degree of suspicion for sinus disease in pregnancy that is
marked by persistent nasal symptoms that are unresponsive to conservative
measures, such as nasal rinsing and recommended nasal/sinus medications.
The diagnosis and management of bacterial sinusitis during pregnancy is de-
scribed elsewhere in this issue.
Patulous eustachian tubes
Complaints of ear congestion, fullness, or stuffiness are encountered fre-

quently during pregnancy. They may be due to eustachian tube dysfunction that
is associated with rhinitis or they may represent a unique condition—patulous
eustachian tubes—that occurs most frequently as a consequence of pregnancy.
Clinical clues to this disorder are aggravation of symptoms by the upright position,
exercise, and nervousness, as well as a sense of disturbed hearing—autophony—
which is hearing one’s voice as if one were talking in an empty barrel. The
frequency of onset of patulous eustachian tubes increases with each trimester, and
typically resolves post partum. Derkay [16] described 20 pregnant volunteers
who had symptoms of eustachian tube dysfunction, 80% of whom had demon-
strable eustachian tube abnormalities by functional testing, such as tympano-
metry. Nineteen percent (3 of 16) had patulous eustachian tubes as demonstrated
by correlating tympanic impedance variation with respiration, which is diagnostic
of this disorder. Because this condition is found mostly in pregnancy and in
women who take birth control pills, hormonal factors may be important in this
disorder; however, a direct cause and effect relationship with any specific hormone
has not been established [17]. The differentiation of patulous eustachian tubes
from the other aforementioned disorders of the middle ear space is important in
that decongestants, typically prescribed for eustachian tube dysfunction, aggravate
patulous eustachian tubes, whereas antihistamines or antibiotics have no effect.
Diagnostic approach
General considerations
In evaluating a pregnant patient who has nasal symptoms, the entire dif-
ferential diagnosis of rhinitis must be kept in mind. A seasonal onset with itching
of the nose or palate and paroxysmal sneezing with congestion and a clear wa-
tery rhinorrhea suggest allergic rhinitis. Similarly, prolonged nasal congestion
and purulent drainage, particularly if lateralized to one nasal passage, is rea-
sonably diagnostic of purulent sinusitis. Bacterial sinusitis, ‘‘rhinitis of preg-
Box 1. Common differential diagnosis of rhinitis during pregnancy
Allergic rhinitis*
Infectious sinusitis
Rhinitis medicamentosa
Pregnancy rhinitis
Eosinophilic nonallergic rhinitis*
Nasal polyps*
Structural nasal obstruction*
* History of same often precedes pregnancy.
nancy,’’ nasal structural problems that are compounded by hormonal mucosa

effects, and rhinitis medicamentosa can mimic allergic rhinitis during pregnancy
when classic seasonal hay fever is not present (Box 1). Rhinitis medicamentosa
is probably encountered more commonly than the in the general population
due to a logical preference pregnant women have for topical vs. systemic medica-
tions to relieve their nasal symptoms. Structural abnormalities, eosinophilic non-
allergic rhinitis, and nasal polyps are also occasionally seen in pregnant women
as a pre-existing condition or even evolve during pregnancy, although there is
nothing to suggest any predisposing influence from pregnancy.
Based on a questionnaire study, some degree of nasal congestion occurs in at
least 22% of pregnant women, although it is not clear how many would seek
medical attention for their symptoms [18]. The authors found such ‘‘pregnancy
rhinitis’’ is more common in smokers, and it seemed to be independent of con-
current atopy, such as hay fever or asthma. These observations suggest a non-
specific reactive mucosa, perhaps from hormonal influences. This syndrome of
nasal congestion (discussed in depth elsewhere in this issue) develops most
prominently in the second and third trimesters, and usually disappears within
5 days post partum, although any accompanying eustachian tube dysfunction
may persist for an additional 4 to 10 weeks. Knowledge of the possible etiologies
of rhinitis in pregnancy allows the treating physician to dictate a logical, direct,
and cost-effective diagnostic scheme.
Evaluation
The combination of a carefully directed history, physical examination of the

nose, and limited laboratory testing commonly suggests the etiology of rhinitis in
pregnancy (see Box 1). Some good questions to ask, other than the description
of symptoms, include the following:
Has the patient had allergic rhinitis in the past and, if so, is this the usual season?
Does the patient have a history of nasal symptoms before pregnancy and, if so,
are they worse now?
Is there purulence, especially in the morning upon arising?

Are the symptoms lateralized to one side?
Is the sense of smell diminished or absent (common in nasal polyps or
chronic sinusitis)?
Is the patient using a decongestant nasal spray?
The physical examination of the nose can be illuminating and often is omitted.
Anatomic findings, such as septal deflections, anterior middle meatal polyps,
boggy paleness or erythema of the turbinate mucosa, and turbinate hypertrophy,
help to define the source of nasal symptoms.
Laboratory testing should be restricted, given the limited nature of pregnancy.
Still, an accurate diagnosis allows for more specific and directed therapy, and
there are some helpful simple maneuvers. For example, nasal cytology can be an
extremely helpful noninvasive approach in pregnancy. Expelling mucus onto a
slide, fixing in alcohol, and staining with Hansel’s or Wright-Giemsa stain can
provide considerable insight into etiologies. The presence of sheets of neutrophils
and bacteria suggests purulent sinus disease. The presence of eosinophils in the
nasal mucosa or secretions is strong circumstantial evidence for an allergic eti-
ology, eosinophilic nonallergic rhinitis, or polyps, and more accurately directs
additional investigative procedures and treatment. If identification of sensitivity
to a potential allergen (eg, house dust mite, animal dander) would be useful for
formulating avoidance instructions, in vitro methodology, such as selective
in vitro (eg, radioallergosorbent test [RAST] or ELISA) testing is useful [19].
Comprehensive allergy skin testing during pregnancy is not recommended be-
cause of the small risk of anaphylaxis and subsequent adverse fetal effects
[20,21]; however, scratch or prick tests to inhalant allergens carry little risk of
anaphylaxis. Under carefully controlled conditions, limited scratch or prick tests
to inhalants (eg, animal dander, dust mite) can be preformed in pregnancy [22].
They only should be performed after inconclusive RAST testing, and only when
the results cannot wait until the pregnancy is completed and are expected to have
substantial therapeutic implications [23].
The presence of purulent nasal discharge, facial pain or discomfort, and nasal
congestion strongly suggest purulent sinusitis; however, rhinitis that is unaccom-
panied by any of these ‘‘classic’’ findings may still be based on sinus disease
[24]. In such circumstances, the diagnosis of sinusitis would escape detection un-
less an imaging study or maxillary antral puncture and culture is pursued. Limited
sinus radiographs or maxillary antral washings can be considered when deemed
necessary for diagnostic confirmation.
Although physicians are rightfully cautious about ordering radiographs during
pregnancy, the threshold dose of pelvic radiation exposure for induction of a
congenital defect has been considered to be 0.1 Gy, which is more than 1000-fold
greater than the amount of radiation that is received from routine diagnostic
radiologic studies [25]. Therefore, the risk of a single radiographic procedure to
the developing fetus is small. As with any medical intervention in a patient,
the benefit to risk ratio must be weighed carefully. To consider imaging in the
gravid patient, several factors should be considered. These factors include the
total amount of radiation exposure during the pregnancy (considering occupa-
tional exposure to radiation as found in flight attendants and pilots or frequent
airline fliers) and other nonradiation imaging options. Several organizations
have commented on radiation risks and limits in the pregnant patient, including
the American College of Obstetricians & Gynecologists (ACOG) and the U.S.
National Council on Radiation Protection and Measurement (NCRP) [26,27]. The
ACOG Committee noted that fetal risks of anomalies, growth restriction, or
abortions are not increased with radiation exposure during pregnancy of less than
0.05 Gy [26]. The NCRP, however, recommends a limit of 1 mSv over a 40-week
period [28].
Most imaging is far below the 0.05-Gy risk limit. A limited sinus CT in
children with 12 to 15 coronal sections 3- to 5-mm thick provides radiation
exposure of less than 0.005 Gy [29]. A screening CT scan of the sinus, as done at
most facilities with only 4 to 6 sections, decreases the radiation dose even further.
The amount of exposure to the fetus from a Waters and Caldwell view of the
mother is less than 0.0000007 Gy. The most sensitive time period for central
nervous system teratogenesis is between 10 and 17 weeks of gestation. Ra-
diologic testing should be avoided during this time if possible, and alternative
diagnostic measures should be pursued. Rare reported consequences of pre-
natal radiation exposure include a slight increase in the incidence of childhood
leukemia and, possibly, a small change in the frequency of genetic mutations
[30,31]. Appropriate counseling of patients is mandatory before radiologic stud-
ies are performed.
In circumstances in which allergic rhinitis or sinusitis is suspected but the phy-
sician or patient is reluctant to undergo additional diagnostic studies, a diagnostic/
therapeutic trial of carefully selected medications, such as antihistamines, nasal
allergy medications, and broad-spectrum antibiotics, may be pursued.
Treatment
General considerations
Data regarding the safety of allergy and asthma medications during pregnancy
are reviewed comprehensively elsewhere in this issue. Information that is par-
ticularly relevant to the treatment of allergic rhinitis during pregnancy is re-
viewed here.
In 1979, the U.S. Food and Drug Administration (FDA) mandated that the
package inserts of all drugs that were approved after November 1, 1980 must
include all available information about their teratogenic and nonteratogenic ef-
fects. A drug classification system was developed using five pregnancy pre-
caution categories: A, B, C, D, and X [32]. The classification system is based
on the degree of risk of teratogenic effects on the fetus as shown by animal and
Table 1
Food and Drug Administration format for labeling human prescription drugs
Category Description of risk
A Well-controlled human studies have failed to demonstrate risk to the fetus.
B Either animal studies show no fetal risk and no human data are available, or
animal studies show a risk but human studies do not show fetal risk.
C Either animal studies indicate a fetal risk and there are no controlled studies in
humans, or there are no available studies in humans or animals.
D Studies show fetal risk in humans, but potential benefits may outweigh the
potential risk in certain situations.
X Studies in animals or humans, or based on human experience show definite
fetal risk.
human clinical data (Table 1). The safest drugs are those in Category A. No
rhinitis medication that has been labeled since 1980 meets the requirements for
pregnancy category A: ‘‘adequate and controlled’’ studies in animals and humans
show no increased risk. Therefore, product labels suggest that medications for
allergic rhinitis, for example, should be avoided in pregnancy because of the
lack of data on fetal safety, although most of the agents have human data that
refute this conclusion. Such limitations represent a major problem for physicians
who treat rhinitis during pregnancy. An effort is being made to replace the current
FDA letter ratings with narrative statements that summarize and interpret existing
teratogenicity data and provide estimates of potential teratogenic risk.
Data sources for drug safety in pregnancy
To help physicians cope with the lack of adequately controlled data and the
difficult medico-legal environment under which most of them practice, several
groups recently published guidelines regarding the use of medications to treat
rhinitis during pregnancy. One comes from the Motherisk Program at the Hospital
for Sick Children, at The University of Toronto concerning the treatment of
allergic rhinitis in pregnancy [33]. The second is a position statement concerning
the use of asthma and allergy medications during pregnancy from a joint com-
mittee of the ACOG and the American College of Allergy, Asthma, and Immu-
nology (ACAAI) [34]. The third comes from the updated NAEPP guidelines
for the management of asthma during pregnancy, in which a section on rhinitis
treatment is included [35]. The following drug information was derived from
these statements and other more recent published reports.
Topical and oral decongestants
Intranasal and ophthalmic decongestants are divided into short-acting agents

(phenylephrine), intermediate-acting agents (naphazoline and tetrahydrozoline),
and long-acting agents (oxymetazoline and xylometazoline). Each of these drugs
carries an FDA category C rating. Data from the Drug Epidemiology Unit of the
Boston Collaborative Perinatal Project and a case-control study reported a sta-

tistically significant association between phenylephrine use in pregnancy and
the occurrence of congenital malformations [36]. A retrospective cohort study
and two case-controlled studies could not confirm such associations [37–39].
These studies also failed to demonstrate adverse effects from the intermediate-
and long-acting topical decongestants. Limited data suggest that for the oc-
casional episode of nasal congestion that interferes with sleep, oxymetazoline
HCl drops or spray can be used as minimally as possible, preferably after the first
trimester and not during labor. Two older reports on the effect of nasal de-
congestants on fetal circulation must be kept in mind. Baxi and colleagues [40]
showed that repeated use of a long-acting sympathomimetic amine, in the form
of a nasal spray, was associated with a nonreactive nonstress test and late de-
celerations in a patient at 41 weeks of gestation. There was a gradual disap-
pearance of the changes 6 hours after the last dose. A later study examined the
effects of a single dose of intranasal oxymetazoline on maternal and fetal indices
[41]. There were no significant changes in the maternal blood pressures or pulse
rates, and blood flow velocities did not change significantly from baseline for the
uterine artery, fetal aorta, or umbilical artery circulations. These investigators
concluded that no acute changes in the maternal or fetal circulations occurred
in uncomplicated pregnancies after a single dose of oxymetazoline. The risk
of rhinitis medicamentosa with continued use of this agent beyond 3 to 5 days
should be emphasized.
The most commonly used oral decongestant, pseudoephedrine, carries an FDA
class C rating. Cohort studies, including 2509 pseudoephedrine exposures, re-
vealed a congenital malformation rate of approximately 2.3%, which was not
increased over the expected incidence [42,43]. Recent case-control studies found
a statistically significant association between the use of pseudoephedrine or
phenylpropanolamine and the risk of developing gastroschisis, a rare disorder that
involves failure of closure of the abdominal wall [44]. The joint ACOG and
ACAAI committee Position Statement emphasized that, even if the relative
increased risk is 10-fold, the rate of gastroschisis is so low (1–2 per 10,000 live
births) that the absolute risk in infants who were exposed to oral decongestants
during the first trimester would not be greater than 20 per 10,000 live births.
Oral decongestants, either alone or in combination with antihistamines, should
be avoided in the first trimester ‘‘unless the expected benefit is large and unique’’.
Pseudoephedrine, 30 to 60 mg every 6 hours or 120 mg time release capsule
every 12 hours, can be considered after the first trimester when the risk of
gastroschisis and vascular disruption has passed. There is a theoretic risk that oral
a-adrenergic agents could induce uterine vascular constriction; however, ad-
ministration of single doses of pseudoephedrine did not cause any alteration in
uterine or fetal Doppler blood flow in one study [45].
There are no specific data available concerning the use of decongestants
during lactation. Pseudoephedrine does pass into the breast milk. It is recom-
mended that only the short-acting form be used, and taken just after breastfeeding
to minimize the concentration in breast milk. As with any medication that is taken
while breastfeeding, the mother should be advised to look for signs of toxicity
in her infant. In the case of decongestants, this typically would be irritability.
Antihistamines
Oral and intranasal

Patients who have known eosinophilic allergic or nonallergic rhinitis that is
accompanied by prominent sneezing and rhinorrhea may benefit from anti-
histamine therapy. In general, there are no human data to suggest that anti-
histamines, as a group, have any deleterious effect on pregnancy, regardless of
when they are taken. Tripelennamine, 25 to 50 mg as needed every 6 hours to a
maximum of 200 mg/d, and chlorpheniramine, 4 to 24 mg/d in divided doses,
have been recommended as the ‘‘safest’’ antihistamines for use during pregnancy
based on available animal and human studies, FDA class B rating, and the
‘‘antiquity’’ of these drugs [46,47]. More recently, loratadine or cetirizine have
been recommended because of reassuring animal and human data [48]. There are
few human data reported regarding fexofenadine and none regarding azelastine
in pregnancy.
The regular maternal use of first-generation antihistamines at the time of
delivery poses a different type of potential risk. Parkin described a 5-day-old
infant who had tremulousness and diarrhea following the maternal ingestion of
150 mg of diphenhydramine daily throughout pregnancy [49]. A mother who
used 400 mg of hydroxyzine daily throughout her pregnancy gave birth to an
infant who demonstrated a transient narcoticlike withdrawal symptom complex
[50]. Finally, maternal antihistamine use has been associated with retrolental
fibroplasia in infants with a birth weight of less than 1750 g [51]. These data
suggest that the regular maternal ingestion of antihistamines, especially in high
dosages, should be terminated as soon as possible before delivery in an attempt
to minimize neonatal withdrawal risk; it should be avoided altogether in women
who are at risk for delivery of very low birth weight infants.
Some adverse effects might be expected from breast milk that contains
maternally ingested antihistamines. Rarely has this proven to be the case; irri-
tability is the most common observation in approximately 10% of mothers sur-
veyed [52]. A report incriminated clemastine as the cause of drowsiness and
irritability in a nursing 10-week-old infant [53]. Clemastine concentrations in
breast milk were 25% to 30% of the maternal serum values, but none could be
detected in the infant’s serum. The infant showed resolution of symptoms within
24 hours of drug withdrawal. Maternal concentrations of loratadine in breast
milk are unlikely to present a hazard to the nursing infant [54].
Ophthalmic antihistamines
The ophthalmic antihistamines, antazoline, azelastine, ketotifen, levocabas-
tine, olopatadine, and pheniramine, carry FDA category C ratings. There are no
published data on their safety during pregnancy.
Antihistamine–decongestant combinations
The physician should be aware that many antihistamines come combined with
decongestant preparations because the former have little or no effect on con-
gestion. Many patients who have rhinitis would benefit from the addition of
pseudoephedrine to the treatment plan after the first trimester, when there is
no further risk of gastroschisis (after the fourth month). Similarly, topical de-
congestants will help ‘‘get the red out’’ as an ophthalmic preparation.
Corticosteroids
Systemic
First-trimester maternal use of oral corticosteroids has been associated with
an increased risk for oral clefts [55–57]. In addition, the use of oral cortico-
steroids in patients who have asthma was associated with an increased risk of
preeclampsia and prematurity, although it is difficult to differentiate adverse ef-
fects that are due to the drug itself from the effects of the more severe asthma
that requires systemic steroids (see the article by Namazy and Schatz elsewhere in
this issue). Systemic corticosteroids rarely, if ever, should be needed for the treat-
ment of allergic rhinitis during pregnancy.
Topical
Although published human data on the intranasal use of corticosteroids is
sparse, the topical use of poorly absorbed and ‘‘first-pass metabolized’’ cor-
ticosteroid derivatives, such as beclomethasone, budesonide, mometasone, tri-
amcinolone, fluticasone, and flunisolide, for allergic rhinitis during pregnancy,
especially after the first trimester, seems to be justified. Because of the metabolic
characteristics of these drugs, little, if any, would be expected to reach the fetus
during maternal intranasal use, but no specific information is available. Certainly,
all of the intranasal steroids cause adverse effects when injected into animals.
Still, the apparent safety of inhaled budesonide in the management of asthma
during pregnancy suggests that the intranasal route of this drug also should be safe
[58–60]. Based on these reassuring data, the FDA recently assigned a category B
rating to intranasal budesonide. For patients who have significantly symptomatic
nasal polyposis or eosinophilic rhinitis, intranasal budesonide should be con-
sidered; however, none of the intranasal corticosteroids seems to have significant
systemic side effects at therapeutic dosages [61]. This led the joint ACAAI-
ACOG committee to state that it is ‘‘not unreasonable to continue an intranasal
corticosteroid different than beclomethasone or budesonide in a patient who is
well-controlled on that drug before pregnancy and continues to require such
therapy’’.
Lactation
With the exception of extremely high parenteral dosages in status asthmatics,
the use of corticosteroids in the lactating mother poses no substantial threat to the
infant. A 50-mg dose of prednisone in the lactating mother would transfer, to the
neonate, less than 20% of its daily physiologic corticosteroid requirement [62].
There are no data concerning the passage of topical corticosteroids into the breast
milk, but one would not expect substantial breast milk levels or any increase
in risk.
Cromolyn sodium
Animal and human data suggest that cromolyn sodium is probably safe in
pregnancy, and it carries an FDA category B rating. There are no pregnancy data
specifically on intranasal or ophthalmic use. Although no controlled terato-
genicity studies have been published specifically with these routes of sodium
cromoglycate, three human studies that involved 638 pregnancies failed to dem-
onstrate any increased risk for congenital defects, even if there was exposure
to inhaled cromolyn sodium for asthma in the first trimester [63]. Furthermore,
little systemic absorption of cromolyn is seen with topical application. For
women who have allergic rhinoconjunctivitis, intranasal or ophthalmic cromolyn
sodium may be considered a first-line treatment before moving on to more
systemic or stronger medications.
Leukotriene modifiers
Zileuton, an inhibitor of 5-lipoxygenase pathway, is an FDA category C drug

with adverse effects in animal studies. Montelukast, which selectively binds to
CystLt1 receptors, and zafirlukast, which competitively binds LtD4 and LtE4
receptors, are listed as FDA category B based on reassuring animals studies. The
package insert now lists montelukast as indicated for treatment of seasonal al-
lergies and asthma, whereas zafirlukast is still only indicated for the treatment
of asthma. Although there are reassuring animal studies, human data are in-
adequate; it is recommended that montelukast or zafirlukast be used in pregnancy
only if it is needed (eg, in patients who have recalcitrant asthma who have
benefited clearly from the drug). The use of montelukast for allergic rhinitis in
pregnancy cannot be supported because there are alternative treatments with
equal or greater efficacy that have much more data on human gestational safety.
Montelukast is excreted in rat milk, but there are no comparable human
data; therefore, caution is advised. The only human data for lactation in this class
of drugs are for zafirlukast; according to the package insert, it reaches a steady-
state concentration in the breast milk that is approximately one fifth of the se-
rum concentration.
Ancillary measures: humidification/cleansing, structural modification, and

avoidance maneuvers
Nasal irrigation methods deserve mention as a useful nonpharmacologic mo-

dality in the treatment of sinusitis during pregnancy. This can take the form of a
topically applied nasal saline mist that is available over the counter, tepid physio-
logic saline, or hypertonic saline that is washed through the nose, using a bulb
syringe, ear syringe, or various squeeze bottles (eg, Sinus Rinse), or more
vigorously with a Water Pik and special nasal adapter. There is little consensus
regarding a uniform protocol for nasal irrigation. It is clear that these techniques
improve nasal hygiene, reduce symptoms of postnasal drainage, and generally
are soothing to the nose. There is some evidence that hypertonic saline delivered
by way of a standard Teledyne Water Pik (Fort Collins, Missouri) device has
advantages of improving mucociliary clearance and sinusitis outcomes [64,65].
Furthermore, there is the suggestion that pulsatile saline delivery using a bulb
syringe or Sinus Rinse is more effective in sinusitis cases than is saline delivered
by way of a nasal spray, such as Ocean Spray [66,67].
Other nonpharmacologic modalities include the use of an external nasal dila-
tor at night and radiofrequency reduction of turbinate size. The external dilator
has been investigated in gestational nasal congestion and was reported to be
effective [68] Radiofrequency ablation, although considered to be a safe and
effective procedure, has not been studied in the pregnant population, other than in
isolated case reports [69,70]. Nevertheless, this in-office technique should be
considered in any pregnant patient who is suffering from sleep disturbance and
discomfort, despite all of the other conservative measures that have been enacted,
especially if significant rhinitis medicamentosa has occurred.
Avoidance of irritants, such as smog and smoke, by staying indoors on high-
risk days or through the purchase and use of an HEPA air filter should be con-
sidered, depending on the clinical circumstances. For the pregnant patient who
has known allergic disease, allergen avoidance is particularly important. Avoid-
ing known allergens, when possible, will improve maternal well-being and mini-
mize the need for pharmacologic intervention.
If all pertinent allergens have not been identified before the pregnancy in the
allergic patient, identification of the offending agents may be of benefit. Because
skin testing with potent antigens may be associated with systematic reactions,
and because abortions and other adverse fetal effects have been associated with
anaphylaxis, it generally should be replaced during pregnancy with in vitro
methods, such as RAST or ELISA tests [71,72]. Historical information often can
be used to suggest if house dust, mold, animal dander, or pollen may be involved.
Avoidance instructions can be given empirically in these circumstances; however,
in selected cases, especially when dealing with indoor animals, selected in vitro
testing may be necessary to demonstrate the need for more vigorous avoid-
ance maneuvers.
Immunologic management
Allergen immunotherapy is an effective method for treating seasonal and pe-

rennial allergic rhinitis. Reduction of the severity of rhinitis or coexisting asthma,
and less need for medications is useful in the allergic pregnant patient. Ongoing
allergen immunotherapy can be maintained during pregnancy. Brief studies and

anecdotal reports from the 1940s suggested a slight increased risk of spontaneous
abortion [34,73]; however, a series of similar reports and studies over the next
several decades suggested that the use of pollen and dust immunotherapy was
not associated with any adverse fetal outcomes [74–76]. More recently, two retro-
spective cohort studies failed to detect any negative association between immu-
notherapy during the first trimester of pregnancy and congenital malformations
[77,78].
Immunotherapy can be considered safe for the mother and fetus during preg-
nancy [21,79]; however, because of the risk of anaphylaxis, the initiation of
immunotherapy during pregnancy should be avoided [80]. Most investigators
recommend that allergen immunotherapy be continued in patients who become
pregnant and have experienced clinical benefit without systematic reactions
[81]. To minimize the risk of a future systematic reaction, consideration should be
given to decreasing the maintenance dosage and stopping any build-up of antigen
dose routinely when the patient and physician become aware of the pregnancy.
Summary
Rhinitis, including allergic rhinitis, in pregnancy represents a challenge to the

physician in terms of its diagnosis and therapy. Although several unique in-
fluences of pregnancy adversely affect nasal mucosa, there is growing recog-
nition that most symptomatic nasal problems are expressions of diagnostic
entities that have been or will be experienced by the patient in the nonpregnant
state. In approaching gestational rhinitis, emphasis should be placed on making
an early, accurate diagnosis so that limited, specific, and informed medicinal
intervention can be used. Simultaneously, the physician should keep in mind that
rhinosinusitis in pregnancy is not necessarily a benign clinical problem. It is im-
portant to remember that upper airway disease, if uncontrolled, has a significant
adverse effect on quality of life and may exacerbate coexisting asthma, which
could affect the pregnancy outcome adversely [82]. Specialty consultation with
otolaryngology or allergy may be necessary in the symptomatic pregnant woman
before an accurate diagnosis and successful therapeutic recommendations can
be made.
The medico-legal atmosphere in the United States poses problems in making
clinical statements about the absolute safety of medicinal intervention during
pregnancy. For physicians who choose to take up this therapeutic challenge,
suitable pharmacologic agents are available to manage the pregnant patient who
has rhinitis or rhinosinusitis to achieve the desired therapeutic outcome. Sug-
gested guidelines for the treatment of allergic conjunctivitis and rhinitis are
summarized in Box 2. In the individual clinical situation, management deci-
sions must be made only after establishing an exact clinical diagnosis, giving full
consideration to the therapeutic risks, benefits, and alternatives, and document-
Box 2. Summary of strategies for the treatment of allergic

rhinoconjunctivitis in pregnancya
All patients: allergen avoidance

Conjunctivitis: ophthalmic cromolyn, supplemented by lorata-
dine or cetirizine as needed
Intermittent rhinitis (symptoms less than 4 days a week or for
less than 4 weeks per year)
Mild: loratadine or cetirizine as needed
Moderate-severe (impairment of sleep, daily activities, school or
work, or troublesome symptoms): intermittent intranasal budeso-
nide, supplemented by loratadine or cetirizine as needed
Persistent rhinitis (symptoms more than 4 days per week and
more than 4 weeks per year)
Mild: intranasal cromolyn supplemented by loratadine or cetiri-
zine as needed
Moderate-severe: regular intranasal budesonide, supplemented
by loratadine or cetirizine as needed; immunotherapyb
a
Classification from the ARIA Workshop Report (Bousquet J,
Van Cauwenberge P, et al. Allergic rhinitis and its impact on asthma.
J Allergy Clin Immunol 2001;108(Suppl):S147–334. J Allergy Clin
Immunol 2001;108:S148).
b
If initiated before pregnancy and successful. Reduce dosage
during pregnancy.
ing this in the patient’s record. Moreover, the physician’s interpretation of the
benefit–risk ratio and the therapeutic decisions based thereon must be fully ex-
plained to, and approved by, the pregnant patient before intervention is initiated.
A significant number of women who suffer from rhinitis of pregnancy are aller-
gic. Under these circumstances, the best first-line approach is avoidance of al-
lergens, which can reduce symptoms significantly. Often, what is chosen first is
either a medication or the decision to allow the pregnant patient to suffer the
symptoms, which can affect the pregnancy outcome adversely. Limited allergy
consultation can be useful under these circumstances to identify pertinent al-
lergens and to direct avoidance effectively. If avoidance is unsuccessful, then,
with the informed consent of the patient and documentation in the chart, medici-
nal intervention can begin as shown (see Box 2). Although many women and
caregivers may choose not to intervene with medications based on fear of tera-
togenicity, such notions are contradicted by a significant amount of medical
evidence. This is especially true of drug intervention for rhinitis and rhinosi-
nusitis after the first trimester.
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26 (2006) 155 – 172
The Management of Respiratory Infections

During Pregnancy
Vanessa Laibl, MD, Jeanne Sheffield, MDT
Department of Obstetrics & Gynecology, University of Texas Southwestern Medical Center,
5323 Harry Hines Boulevard, Dallas, TX 75390-9032, USA
Respiratory infections that complicate pregnancy are encountered frequently,

and they encompass a broad range of disorders. Although respiratory infections
usually are not seen more commonly in pregnancy, they often result in greater
morbidity and mortality secondary to the physiologic adaptations that occur
during pregnancy. Pregnant patients who have one of these disorders require a
higher level of surveillance and intervention.
Pulmonary physiologic adaptations during pregnancy
Pulmonary physiologic changes during pregnancy are discussed in detail else-

where in this issue. As with many of the other organ systems, the respiratory sys-
tem undergoes several adaptations during pregnancy. Tidal volume increases
although the respiratory rate remains unchanged which results in an increase in
minute ventilation that up to 50% higher than in nonpregnant women [1–5].
Minute oxygen uptake also increases, and allows for the increasing oxygen re-
quirements as the pregnancy advances. There is no change in forced vital capac-
ity, lung compliance, or diffusing capacity; however, functional residual capacity
decreases by 15% to 20% at term. Total pulmonary resistance also decreases dur-
ing pregnancy, possibly because of an increase in progesterone levels. Although
overall hemoglobin amount increases and allows for an increase in total oxygen-
carrying capacity, the increase in blood volume—which is disproportionate to
the increase in hemoglobin concentration—results in a physiologic anemia that
E-mail address: jeanne.sheffield@utsouthwestern.edu (J. Sheff ield).
156 laibl & sheffield
decreases the arterial oxygen content by a small amount in the third trimester
[6]. Finally, the diaphragm is elevated as much as 4 cm in pregnancy, and the
transverse chest diameter increases 2.1 cm [7].
Sinusitis
Acute bacterial sinusitis is an infection of the mucosa of the paranasal sinuses

and nasal cavity, and it develops most commonly as a complication of a viral up-
per respiratory infection. It is one of the most common diseases in the outpatient
clinical setting, with annual costs of more than $2 billion in the United States [8].
Acute viral sinusitis is common and usually resolves without treatment; however,
bacterial sinusitis complicates viral sinusitis in 0.5% to 2% of cases [9,10], and
requires antimicrobial therapy to prevent complications. Distinguishing between
viral and bacterial sinusitis can be difficult.
Sinusitis develops when there is inflammatory edema of the sinus mu-
cosa, obstruction of the sinus ostia, and decreased mucociliary activity [9]. This
stasis provides a milieu that is conducive to bacterial growth. Common bacterial
pathogens that are associated with acute bacterial sinusitis include Streptococcus
pneumoniae, H influenzae, Streptococcus pyogenes, Neisseria species, Morax-
ella catarrhalis (more common in children), Staphylococcus aureus, and some
anaerobic bacteria. Fungal sinusitis, primarily aspergillosis, also should be con-
sidered, particularly in women who have a history of immunoincompetence.
Risk factors for the development of acute bacterial sinusitis include a history of
allergic disorders; dental infections; anatomic abnormalities, such as a deviated
septum, nasal polyps, or cleft palate; nasogastric or nasotracheal intubation; baro-
trauma; chemical irritants; cystic fibrosis; and immunodeficiency. Although one
older study suggested an increase in the incidence of sinusitis during pregnancy
[11], no recent data are available that address this issue.
Acute viral and bacterial sinusitis often present with nasal congestion, purulent
nasal or postnasal discharge, sinus pain or pressure over the affected sinus, cough,
sinus headache, fever, and malaise. To distinguish bacterial from viral sinusitis—
a challenging, yet important, distinction because management varies—a person
must have persistence of symptoms for longer than 7 to 10 days. A common find-
ing when bacterial infection develops in the setting of viral sinusitis is a report of
two phases with improvement in between—a ‘‘double sickening’’ sign. A change
in color of nasal discharge from clear/yellow to greenish also is an indicator of
progression to bacterial sinusitis. Transillumination of the sinuses and plain
radiographs of the sinuses may help to confirm sinusitis, but they cannot dis-
tinguish between viral and bacterial sinusitis [12]. CT or MRI should be reserved
for evaluation of complicated sinus cases.
Although uncommon, complications of acute bacterial sinusitis can be se-
vere. Local extension of infection into the sinus bones, orbits, and intracranial
cavity can occur as can central nervous system involvement (ie, meningitis,
brain abscess, and cavernous sinus infection). Appropriate antimicrobial therapy
managing respiratory infections during pregnancy 157
has decreased the incidence of these complications markedly over the last
few decades.
After a diagnosis of acute bacterial sinusitis is made, antimicrobial therapy and
systemic relief should be initiated. Analgesics and antipyretics; decongestants;
and moisturization techniques, including nasal irrigation, steam inhalation, and
warm packs are useful in providing relief. Recommended antimicrobial therapy
to eradicate the bacterial pathogen varies among countries, depending on the
common pathogens and patterns of antimicrobial resistance. In the United States
[13], the American Academy of Otolaryngology-Head and Neck Surgery’s
Guidelines first line of treatment regimens include amoxicillin, amoxicillin–
clavulanic acid, or a second-/third-generation cephalosporin. These are acceptable
regimens in pregnancy and should be given for 10 to 14 days. In penicillin-
allergic patients, a course of one of the macrolides, particularly azithromycin, is
warranted. Macrolide resistance has become a major problem in many European
countries and it is not recommended in these areas. Surveillance in the United
States shows a lower rate of resistance, and macrolides remain an alternative
first-line therapy for patients who have penicillin allergy. In penicillin-allergic
patients, a course of trimethoprim–sulfamethoxazole also may be considered.
Telithromycin, a new antibacterial ketolide with a low propensity for drug re-
sistance, is as effective as any first-line agent and has limited side effects [14].
Listed as pregnancy Category C, no data are available regarding its use during
pregnancy in humans. Alternative regimens for bacterial sinusitis listed in the
American Academy of Otolaryngology—Head and Neck Surgery’s Guidelines
include the fluoroquinolones, but fluoroquinolones are not recommended during
pregnancy and should be avoided if possible.
Bronchitis
Bronchitis is inflammation of the bronchial mucous membranes. Chronic bron-

chitis, defined as a productive cough for more than 3 months per year for at least
2 years, is a major part of chronic obstructive pulmonary disease and rarely
complicates pregnancy. Acute bronchitis is associated with cough that develops
during an upper respiratory tract infection that usually is viral in origin. Most
cases of acute bronchitis are caused by rhinovirus, influenza, and adenovirus.
Other causative organisms include Mycoplasma pneumoniae and C pneumoniae.
Cigarette smoking is the predominant risk factor for chronic bronchitis, and may
play a role in acute disease.
During an acute upper respiratory infection, a cough with occasional sputum
production and low-grade fever may be present. Dyspnea is an uncommon symp-
tom of acute bronchitis. Antibiotics are indicated rarely for acute disease, al-
though they are prescribed frequently; symptomatic relief is paramount. Antibiotic
use should be reserved for suspected bacterial etiology or for women who do not
respond to symptomatic relief. Symptoms should resolve within a few days, al-
though the cough may persist for months. The management of chronic bronchitis
is outside the scope of this article because it rarely complicates pregnancy.
Pneumonia
Pneumonia and influenza combined are the seventh leading cause of death in
the United States, and the number one cause of death from an infectious disease
[15]. More than 5 million cases occur annually, more than 1.3 million persons
require hospitalization, and there were 22 deaths per 100,000 population in 2002
[15]. Although women of reproductive age have much lower mortality, they are
susceptible to pneumonia from bacterial, viral, and fungal sources. Overall,
pneumonia is the primary diagnosis for 4.2% of the antepartum admissions for
nonobstetric causes [16]. Although pregnant women do not acquire pneumonia
more often than do nonpregnant women, it can result in greater morbidity and
mortality because of the physiologic adaptations of pregnancy.
Thus, pregnant patients require a higher level of surveillance and intervention.
In a study by Jin and colleagues [17], the hospitalization rate for community-
acquired pneumonia in pregnant women was 1.51 per 1000 pregnancies. Another
recent report noted a prevalence of 1 per 660 deliveries [18] for community-
acquired pneumonia.
Bacterial pneumonia
Some of the organisms that cause bacterial pneumonia include Streptococcus

pneumoniae, H influenzae, C pneumoniae, Mycoplasma pneumoniae, and Legio-
nella pneumophila. The American Thoracic Society notes that even with exten-
sive diagnostic testing, the etiology cannot be identified in at least 50% of cases.
A gram stain and culture of sputum can be helpful in focusing therapy, but its use
is controversial. Bacterial cultures of sputum have poor sensitivity and specificity
[19]. Of strains identified, Streptococcus pneumoniae is the most common, al-
though the overall incidence is decreasing in women of reproductive age because
of the improved use of pneumococcal conjugate vaccine. Drug-resistant strains of
Streptococcus pneumoniae, particularly b-lactamase–resistant strains, are increas-
ing in prevalence [20].
Mycoplasma pneumoniae is another major cause of bacterial pneumonia in
young adults, and outbreaks are common in institutional-type settings (eg, col-
lege). Persistent cough is common but the disease rarely is fatal. The incidence of
C pneumoniae pneumonia is unknown, although it is most common in school-
aged children. Reinfection throughout life is common and occasionally it presents
in pregnancy.
Risk factors for pneumonia include asthma and other chronic respiratory
diseases, HIV/AIDS, smoking, and drug use [21]. Signs and symptoms of bac-
terial pneumonia in pregnancy are the same as in nonpregnant individuals.
Symptoms include cough (N90%), sputum production (66%), dyspnea (66%),
and pleuritic chest pain (50%) [22]. Signs include fever, crackles, and abnormal
breath sounds. A chest radiograph should be performed in patients who have
the aforementioned findings and in whom pneumonia is suspected. The chest
radiograph will confirm pneumonia, rule out other diagnoses, suggest a possible
cause, and aid in determining the severity of illness. Multilobar pneumonia is
considered a more severe process than is single lobar involvement [19]. Gener-
ally, all pregnant women who have pneumonia are hospitalized for observation
and initial therapy. Work-up should include a complete blood count, electrolytes,
assessment of oxygenation, and blood cultures; however, blood cultures are posi-
tive only 7% to 15% of the time [18,21].
Maternal mortality was reduced greatly with the advent of antibiotics [23,24].
Intravenous antibiotic therapy should be started empirically. Erythromycin
monotherapy is an acceptable initial choice for treatment because it is considered
safe in pregnancy [25]. Treatment success rates of up to 99% have been reported
[18]. If aspiration, gram-negative organisms, or complications that are noted in
Box 1 are suspected or identified, cefotaxime or ceftriaxone should be added to the
erythromycin regimen. In endemic areas that are known to harbor drug-resistant
Streptococcus pneumoniae, a course of fluoroquinolones may be required [26],
although little information regarding the possible human teratogenicity is avail-
Box 1. Complicating factors that are associated with pneumonia
Coexisting chronic conditions (eg, asthma, diabetes, heart disease)

Altered mental status
Vital sign abnormalities
Respiration 30/min
Temperature 398C or 358C
Hypotension
Pulse 125 beats per minute
Laboratory abnormalities
White blood cell count b4000/uL or 30,000/uL
Room air PaO2 b60 mm Hg
Room air PaCO2 N50 mm Hg
Serum creatinine N1.2 mg/dL
Multiorgan dysfunction or sepsis
Radiologic abnormalities
Multilobe involvement
Cavitation
Pleural effusion
Data from American Thoracic Society. Guidelines for the manage-

ment of adults with community-acquired pneumonia. Am J Respir
Crit Care Med 2001;163:1730–54.
able [24]. Most patients have a clinical response within 3 days. Therapy should not
be changed in the first 72 hours unless there is a marked clinical deterioration [19].
Many different complications of bacterial pneumonia have been reported.
Infections at other sites can occur; meningitis, arthritis, endocarditis, empyema,
and pericarditis have been noted in association with pneumonia. Severe cases of
pneumonia can be complicated by sepsis, heart failure, renal failure, and acute
respiratory distress syndrome and require intensive care admission. Obstetric
complications include fetal distress secondary to poor oxygenation and preterm
birth. Munn and colleagues [27] found that women who had pneumonia were
significantly more likely to deliver before 34 weeks. Preterm birth was reported
to be more common when the woman who had pneumonia has some underlying
comorbid condition [28]. Anemia also was reported in several studies of pneu-
monia during pregnancy [18,21,27]. The birth weight of infants who were born
to women who had antepartum pneumonia was significantly less than that of
controls [18,21].
With the increasing number of pregnant women who are infected with HIV,
Pneumocystis carinii pneumonia (PCP) deserves specific mention. This is the
leading cause of AIDS-related death among pregnant women in the United States
[29]. Symptoms include dry cough, dyspnea, and tachypnea. A diffuse infiltrate
is seen on chest radiograph. Ahmad and colleagues [30] reported 22 cases of
PCP in pregnancy. The mortality was extremely high (50%). Fifty-nine percent
required mechanical ventilation. These numbers may be inflated because none
of the patients was on antiretroviral therapy; all were diagnosed with HIV
when diagnosed with PCP. Treatment is with trimethoprim–sulfamethoxazole or
pentamidine. HIV-infected patients with a CD4+ T lymphocyte count of less
than 200/mL, a history of oropharyngeal candidiasis, or an AIDS-defining
illness should receive prophylaxis [31]. The preferred prophylactic regimen is
trimethoprim–sulfamethoxazole, one double-strength tablet per day. Prophylaxis
is 90% to 95% effective [32] in nonpregnant individuals and is expected to be
similarly effective in pregnancy.
Viral pneumonia
Viral pneumonia is caused most commonly by influenza and varicella-zoster

virus (VZV). Influenza is caused by two RNA viruses in the family Ortho-
myxoviridae, influenza A and influenza B. Historically, influenza in pregnant
women has been associated with a higher rate of morbidity and mortality. The
course of influenza in pregnancy was reported first during the epidemic of 1918,
when 1350 cases in pregnant women who had an influenza-like illness were
evaluated. Pneumonia complicated 585 (43%) of the cases. In 52% of these
patients, the pregnancy was interrupted. There were 308 (23%) maternal deaths.
Mortality was highest in the last 3 months of pregnancy, and increased if
complicated by pneumonia [33]. During the influenza epidemic of 1957, 22 preg-
nant women in New York City died from complications of the flu. Pregnant
women accounted for nearly half of the deaths of women of child-bearing age
[34]. During the same epidemic, 11 pregnant women died in Minnesota. All
deaths were attributed to respiratory insufficiency secondary to pulmonary edema
and pneumonia [35]. Mullooly and colleagues [36] reviewed influenza com-
plicating pregnancy from 1975 to 1979. There were four epidemics in that 5-year
period. Pregnant women sought outpatient medical attention for acute respiratory
disease during the influenza season significantly more often than did nonpreg-
nant women.
Influenza infection is epidemic in winter months, and is spread by aerosol-
ized droplets. Particles are created when a person coughs, sneezes, or speaks.
These particles are filtered by the recipient’s nose and pharynx and reach the
alveoli [37].
The clinical presentation of influenza does not seem to be altered by preg-
nancy. The incubation period for influenza is 1 to 4 days with an average of 2 days
[38]. Generally, patients are infectious the day before the onset of symptoms and
for 5 days thereafter. Young children and immunocompromised adults can shed
virus for much longer periods of time [39]. Infants who are infected while in the
hospital can shed virus for up to 21 days [37].
Symptoms of influenza include cough, fever, malaise, rhinitis, myalgias,
headache, chills, and sore throat. Less common symptoms include nausea and
vomiting, otitis, and conjunctival burning. Signs of influenza include fever, tachy-
cardia, facial flushing, clear nasal discharge, and cervical adenopathy. In adults,
fever generally lasts for 3 days with resolution of symptoms normally within
1 week; the cough and malaise may persist for longer than 2 weeks.
Pneumonia, either viral or superimposed bacterial, is a well-recognized com-
plication of influenza. Initially, patients present with respiratory distress in the
case of viral pneumonia. On chest radiograph, diffuse bilateral infiltrates are seen.
Signs of pneumonia include course rales and rhonchi, wheezing, dyspnea, and
tachypnea. Typically, superimposed bacterial pneumonia occurs 2 to 14 days
after symptoms of influenza have resolved. Local consolidation is seen on chest
radiograph with superimposed bacterial pneumonia. Pregnant women who have
influenza pneumonia should be evaluated, and may be treated with one of the
antiviral agents that are approved for the treatment of influenza. The adamantines,
M2 ion-channel inhibitors, include amantadine and rimantadine and have activity
only against influenza A. They may be given within the first 48 hours of symp-
toms to reduce symptom duration. To minimize drug resistance, therapy should
be discontinued within 24 to 48 hours after symptoms resolve, or within 3 to
5 days. The neuraminidase inhibitors are effective in the treatment of influenza A
and B. Oseltamivir, given orally, is approved for treatment and chemo-
prophylaxis. Zanamivir is an inhaled medication that is approved for treatment
only. There have been several reports of bronchospasm in patients who had
asthma who took this drug. Both shorten the duration of symptoms by an average
of 1 day. There are limited data on safety in pregnancy. All four drugs are U.S.
Food and Drug Administration category C, and therefore, should be used only
when the benefits outweigh the risks [25].
VZV is a DNA virus that affects 0.7 per 1000 pregnancies [40]. Pneumonia is
the most common complication in adults, and it occurs in 10% of cases [41].
Before the availability of antiviral therapy, mortality in pregnant women who
had VZV pneumonia was as high as 35% to 40% [42,43]. The mortality in the
era of antiviral therapy is approximately 14% [43,44]. Risk factors for varicella
pneumonia include smoking and the presence of more than 100 skin lesions [41].
Pulmonary symptoms begin 2 to 5 days after the onset of rash and fever.
Symptoms include cough, hemoptysis, dyspnea, tachypnea, and pleuritic chest
pain. Chest radiograph shows diffuse miliary or nodular infiltrates. Treatment is
with intravenous acyclovir, although the value of this has not been proven in
rigorous scientific studies.
Varicella pneumonia has been associated with preterm labor in some studies,
although recent reports have not substantiated this [41,45]. If varicella-zoster
immunoglobulin is given within 96 hours of exposure to varicella, it can attenuate
or prevent infection in susceptible individuals. It is not contraindicated in preg-
nancy. The varicella vaccine is contraindicated in pregnancy because it is a live-
attenuated vaccine.
Severe acute respiratory syndrome (SARS) is caused by a novel coronavirus.
Since 2002, this atypical pneumonia has affected more than 8000 people and has
resulted in more than 800 deaths worldwide [46]. Transmission is by respiratory
droplets or close personal contact. The virus can live in urine and stool for 1 to
2 days. Symptoms are the same in pregnant and nonpregnant women and include
fever, chills, rigors, malaise, and myalgias [47]. Patients are most infectious
during the second week of illness. Most often, chest radiograph findings are
generalized, patchy, interstitial infiltrates [46]. Patients have been noted to have
lymphopenia as well as thrombocytopenia [46,47].
Diagnosis can be made by culture, polymerase chain reaction, ELISA, and
immunofluorescence assay. Guidelines and protocols for diagnostic tests are
available on the World Health Organization web site. Complications of SARS
pneumonia include respiratory failure, superimposed bacterial infections, and
disseminated intravascular coagulation. The largest case series of pregnant
women who had SARS was reported by Wong and colleagues [48] from China.
Twelve pregnant women were infected with SARS between February 1, 2003 and
July 31, 2003. High rates of morbidity and mortality were noted. The case fatality
rate was 25%. A large portion of the cases was complicated by first-trimester
spontaneous abortions, preterm births, and intrauterine growth restriction. No
case of vertical transmission has been reported. Treatment includes broad-
spectrum antibiotics to cover superimposed bacterial infections, high-dose
steroids, and possibly, ribavirin. Ribavirin was shown to have teratogenic effects
in animals [25], and its use in pregnancy has not been established.
Fungal pneumonia
Fungal pneumonia is usually seen in women who are immunocompromised

(eg, HIV infection). Histoplasmosis and blastomycosis are the most common
fungal pneumonias that complicate pregnancy and usually are mild and self-
limited. Cryptococcosis also may present during pregnancy, although meningitis
is more common than pneumonia. Coccidioidomycosis also may cause pneumo-
nia in pregnancy and is associated with erythema nodosum. It occurs frequently
in endemic areas. Most fungal pneumonias present similarly to bacterial and vi-
ral pneumonias, with cough, dyspnea, fever, and chest pain as common com-
plaints. Pregnant women who have complicated fungal infections, including
disseminated disease, are treated with amphotericin B or ketoconazole [49–52],
although the safety data of long-term use in pregnancy are limited [25].
Summary
Regardless of the type of pneumonia, it is important to be aggressive with

monitoring and treatment for the sake of the mother and fetus. Oxygen sup-
plementation should be provided to prevent fetal acidemia. Broad-spectrum
empiric antibiotics should be started before identification of the etiologic agent,
and antibiotic therapy should be tailored to specific organisms as laboratory tests
return. Given that most pregnant women are young and healthy, intense, early
treatment is likely to result in a good outcome.
Tuberculosis
Tuberculosis is a pulmonary infection that is caused by the acid-fast bacillus,

Mycobacterium tuberculosis. Although Mycobacterium bovis, M africanum,
and M microti can cause human disease, M tuberculosis is encountered most
commonly. It is estimated that eight to nine million new cases of tuberculo-
sis occurred worldwide in 2000; more than half occurred in Asia [53]. During
2004, 14,517 cases of tuberculosis in the United States were reported to the
Centers for Disease Control and prevention (4.9 per 100,000); this represented
a 2.3% decrease from 2003 [54]. Most cases (54%) occurred in foreign-
born persons.
Several factors were implicated in the resurgence of tuberculosis in the United
States that occurred in the late 1980s and early 1990s. These included increased
immigration from countries with a high prevalence of tuberculosis, HIV infection,
emergence of resistant strains, poverty, homelessness, drug abuse, and a decline
in tuberculosis-related health services [55]. This increase was accompanied by
an increased frequency of tuberculosis in pregnant women. With appropriate
therapy, pregnancy does not affect the course of tuberculosis adversely; however,
tuberculosis may affect pregnancy outcome adversely. Low birth weight, pre-
term delivery, and increased perinatal mortality rates have been reported in the
setting of incomplete treatment and advanced or extrapulmonary tuberculosis
[56,57].
Transmission
Transmission and infection during pregnancy are believed to be the same as

in nonpregnant women. Mycobacterium tuberculosis is transmitted most com-
monly from person to person by respiratory droplets that are aerosolized during
coughing, sneezing, singing, or speaking. The droplets dry rapidly and may re-
main suspended in the air for several hours. Factors that are associated with the
likelihood of transmission include the intimacy and duration of contact, the
degree of infectiousness of the case, and the shared environment of the contact.
Patients who have sputum smear–negative/culture-positive tuberculosis are less
infectious, and those who have culture-negative pulmonary disease and extra-
pulmonary tuberculosis are noninfectious.
Droplets gain direct access to the terminal air passages when inhaled; ap-
proximately 10% reach the alveoli. There, activated alveolar macrophages ingest
the bacilli. If the bacilli multiply, their growth quickly kills the macrophages,
which lyse. Usually, these initial stages of infection are asymptomatic. Two
to 4 weeks after infection, two additional host responses develop—a tissue-
damaging response and a macrophage-activating response. Large numbers of
activated macrophages accumulate at the site of the primary lesion, and granu-
lomatous lesions are formed [58,59]. These lesions consist of lymphocytes and
activated macrophages. Macrophages that contain bacilli travel to the lymph
nodes and then to the rest of the body.
Many patients are infected with Mycobacterium tuberculosis, but do not have
the active form of disease. In patients who go on to have active disease, the
macrophage-activating response is weak, and, therefore, mycobacterial growth
only can be inhibited by an intensified tissue-damaging response. Because the
surrounding tissue is damaged progressively, the lesion enlarges. Most infected
individuals who develop active disease do so within 1or 2 years after infection.
Clinical illness shortly after infection is termed primary tuberculosis. Dormant
bacilli may persist for years and then become reactivated. This is referred to as
secondary or postprimary tuberculosis [60].
It is estimated that approximately 10% of infected persons eventually de-
velop active tuberculosis. Groups who are at risk for infection and progression
to active disease are listed in Box 2. Factors that place patients at high risk for
developing active disease include age, HIV coinfection (suppressed cellular im-
munity), silicosis, malignant neoplasms, hemophilia, chronic renal failure, and
insulin-dependent diabetes mellitus [61–65]. Among infected persons, the inci-
dence of tuberculosis is highest during late adolescence and early adulthood. The
incidence among women peaks at 25 to 34 years of age [60].
Clinical course
Clinical manifestations of tuberculosis usually include fever, night sweats,

cough, weight loss, anorexia, general malaise, and weakness. Massive hemop-
tysis can occur as a result of erosion into a pulmonary vessel in the wall of a
Box 2. Groups at high risk for tuberculosis
Increased risk for exposure
Immigrants from areas that are endemic for tuberculosis

Residents of long-term care facilities and nursing homes
Healthcare workers
Incarcerated persons
Homeless persons
Intravenous drug users
People living in crowded conditions
Increased risk for active disease
Immunocompromised patients, including those who have

HIV infection
Infants
Elderly
Patients who have:
Diabetes mellitus
Hemophilia
Chronic renal failure
Malignancy
Silicosis
tuberculin cavity. Other findings include wasting, rales, rhonchi, and clubbing of
fingers because of hypoxia. On chest radiograph, the classic finding is that of an
upper lobe infiltrate or cavity; however, the film may be normal or have other
findings, such as nodules or diffuse infiltrates. Cavitation or mediastinal lymph-
adenopathy also may be seen.
Although any organ system can be affected, the extrapulmonary sites that
are involved most commonly in tuberculosis include lymph nodes, pleura, geni-
tourinary tract, bones and joints, meninges, and peritoneum. Extrapulmonary
tuberculosis is being seen more often because of HIV coinfection. Five to 10%
percent of pregnant women who have tuberculosis have extrapulmonary disease.
Miliary tuberculosis is due to hematogenous spread of the bacilli. It may
occur with recent infection or reactivation of old disseminated foci. Common
symptoms include weakness, fever, and weight loss. Miliary tuberculosis can be a
difficult diagnosis to make because there may be no radiographic findings [66].
If present, radiologic findings may include large infiltrates, interstitial infiltrates,
and pleural effusions. A sputum smear for acid-fast bacilli is negative in 80% of
cases. Hematologic abnormalities that are seen with miliary tuberculosis include
anemia, leukopenia, neutrophilic leukocytosis, and polycythemia [67]. Dissemi-
nated intravascular coagulation may be present. In patients who have severe

hepatic involvement, abnormal liver enzymes can be seen. A purified protein de-
rivative (PPD) test is negative in up to half of cases. Often, bronchoalveolar la-
vage, transbronchial biopsy, or tissue biopsy is necessary to confirm the diagnosis.
Congenital and neonatal tuberculosis
Congenital tuberculosis is a rare and often fatal disease; it usually is acquired

by way of hematogenous spread to the fetus through the placenta and umbilical
cord. Bacilli have been retrieved from the decidua, amnion, and chorionic villi
[68]. A fetus also may become infected with Mycobacterium tuberculosis by
ingesting amniotic fluid [69,70]. Hematogenous acquisition commonly results in
granulomatous complexes within the liver. Acquisition by way of aspiration
results more often in complexes in the lungs or gastrointestinal tract [71]. Beitzke
[68] detailed criteria for congenital tuberculosis: (1) firm diagnosis of tuber-
culosis in the newborn, (2) primary complex in the newborn’s liver, or (3) if no
primary complex is identified in the liver, tuberculous lesions must be docu-
mented in the first few days of life to exclude extrauterine infection. In many
cases, the newborn is diagnosed before the mother. Hageman and colleagues [72]
reviewed cases of congenital tuberculosis. The most common signs and symp-
toms, in descending order, were respiratory distress, fever, liver/spleen enlarge-
ment, poor feeding, lethargy, and lymphadenopathy. In this review, neonatal
mortality was 46%; however, in three quarters of the deaths, there was no treat-
ment because the diagnosis was made post mortem. Initially, tuberculin testing
may be negative and may remain so for several months. Neonatal tuberculosis is
far more common, and occurs when the newborn is infected after exposure to the
infected mother or other family member.
Diagnosis
Current guidelines for screening for tuberculosis include skin testing of

women who are in high-risk groups (Box 3). The PPD tuberculin skin test is
the only test that can detect Mycobacterium tuberculosis infection reliably in
asymptomatic persons. The test becomes positive 2 to 12 weeks after infection
[73]. Sensitized CD4+ lymphocytes travel to the site, proliferate, and produce
cytokines; consequently, a raised, erythematous area forms. The size of the
reactive area determines whether the test is positive. The size of the reactive
area that is used to define a positive test varies with risk factors. Induration of
at least 5 mm is used for patients who have HIV infection, recent contact with
a person with active tuberculosis, organ transplant, or fibrotic changes on chest
radiograph that are consistent with old tuberculosis. An induration of at least
10 mm is used in patients who are recent immigrants (within 5 years) of high
prevalence countries, intravenous drug users, residents or employees of high-risk
settings (eg, jails, nursing homes, shelters, hospitals), or who have conditions
that are associated with a high risk of disease after infection. An induration of
Box 3. High-risk groups that should undergo tuberculosis screening
HIV-infected persons
Persons who have medical risk factors that are known to in-
crease the risk of disease if infection has occurred
Close contacts of a person who is known or suspected to
have tuberculosis
Foreign-born persons from areas where tuberculosis is common
Residents and employees of high-risk congregate settings
Health care workers who serve high-risk clients
Medically underserved, low-income populations (eg, Asian, His-
panic, African, and Native American)
Persons who inject illicit drugs
Persons who have a history of inadequately treated tuberculosis
Data from Centers for Disease Control and Prevention. Interactive

core curriculum on tuberculosis: what the clinician should know.
Available at: http://www.cdc.gov/nchstp/tb/webcourses/CoreCurr/
index.htm.
at least 15 mm is used for low-risk people [74]. The test has low sensitivity
and specificity in the case of active tuberculosis. In addition, false negative results
are common in immunocompromised patients. Patients who have received the
bacille Calmette-Guérin vaccine can have a false-positive test, although the skin
induration rarely exceeds 20 mm in false positive results [75].
All pregnant women who have a positive test should undergo a chest ra-
diograph with abdominal shield to assess for evidence of disease. Hemato-
logic findings include anemia, leukocytosis, and occasionally, hyponatremia.
In patients who have suspected active pulmonary tuberculosis, three sputum
specimens—collected early in the morning—should be taken for acid fast
bacillus (AFB) smear and mycobacteriology culture. If tissue is obtained for cul-
ture, it is important that it not be put in formaldehyde because this compromises
test accuracy. Definitive diagnosis depends on the isolation and identification of
Mycobacterium tuberculosis from a diagnostic specimen, such as sputum or tis-
sue. Culture is a time-consuming process because Mycobacterium tuberculosis
can take 4 to 8 weeks to grow; however, it is important because drug suscep-
tibilities can be determined and treatment can be optimized for the individual
patient [76].
Treatment
The treatment of tuberculosis in pregnancy varies, depending on disease sta-

tus (ie, PPD positive alone versus active disease) and drug resistance testing in
endemic areas. If a pregnant woman has a positive PPD that indicates infec-
tion but no evidence of active disease, treatment with isoniazid (INH) may
be withheld until after delivery because of the increased risk for hepatotoxicity
[77,78]. Pregnant women who are infected with HIV should start therapy im-
mediately, because there is an 8% annual risk for progression to active disease.
Pregnant women who have other risk factors for progression, including known
recent skin-test convertors, also should not delay initiation of therapy [74].
Management of active pulmonary tuberculosis during pregnancy is similar
to that in nonpregnant women. INH, rifampin, and ethambutol (EMB) should be
used in initial treatment regimens. If local prevalence of isolates that are resistant
to INH is high, pyrazinamide should be added to this regimen until the results of
susceptibility testing are available. These medications cross the placenta, but
were not shown to have teratogenic effects [25]. Women who are being treated
can breastfeed. Although these medications are found in breast milk, the amount
of drug does not reach therapeutic levels, and is not sufficient for treatment of the
newborn [79]. Pregnant and postpartum women should receive pyridoxine.
Table 1 lists the medications that are used in the treatment of tuberculosis.
INH dosing can be daily or two to three times per week. Side effects include
aminotransferase elevations, hepatitis, peripheral neurotoxicity, and a lupuslike
syndrome. Hepatitis seems to be more common in pregnant patients who take
INH; thus, liver enzymes should be evaluated frequently and pyridoxine should
be administered. The dose of pyridoxine in prenatal vitamins can vary, and
generally, the dose is inadequate for this purpose. Rifampin also is a first-line
agent with dosing once daily or two to three times per week. Side effects include
rash, nausea/vomiting, and hepatitis. Patients must be warned that rifampin
will turn urine, sweat, sputum, and tears orange [80,81]. EMB is a first-line drug
for treating all forms of tuberculosis. It is included in initial treatment regimens,
primarily to prevent emergence of rifampin resistance when primary resistance
to INH may be present. Adverse effects include retrobulbar neuritis, peripheral
neuritis (rare), and skin reactions that require discontinuation of the drug. EMB is
considered safe for use in pregnancy [25]. Pyrazinamide is a first-line agent that
is highly active against dormant and semidormant bacterial populations [82].
Table 1
Medications for the treatment of tuberculosis in pregnant women
Drug Interval and duration Side effects and warnings
Isoniazid Daily or 2–3/wk Hepatitis, GI distress, seizures, peripheral neuropathy
6 or 9 months
Rifampin Daily or 2–3/wk Hepatitis, GI distress, purpura, febrile reactions,
2–4 months orange secretions
Ethambutol Daily or 2–3/wk Retrobulbar neuritis, peripheral neuritis, skin reactions
2 months
Pyrazinamide Daily or 3/wk GI distress, rash, arthralgias
2 months
Abbreviation: GI, gastrointestinal.
Hepatotoxicity that is attributable to standard doses of pyrazinamide (PZA) oc-

curs in approximately 1% of cases [83]. Mild anorexia and nausea are common.
Transient morbilliform rash also can occur but usually is self-limited. There is
little information about the safety of PZA in pregnancy. The benefits of PZA may
outweigh the possible risks in areas in which drug-resistant tuberculosis is en-
demic [84,85]. Streptomycin should be avoided in pregnancy because of an in-
creased risk of congenital deafness.
References
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518 – 24.
[2] Gazioglu K, Katreider NL, Rosen R, et al. Pulmonary function during pregnancy in normal
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Asthma and Rhinitis During Pregnancy

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Immunol Allergy Clin N Am

Asthma and Rhinitis During Pregnancy

Rafeul Alam, MD, PhD

I am honored to serve as the Consulting Editor for the Immunology and

Rafeul Alam, MD, PhD

Asthma and Rhinitis During Pregnancy

Michael Schatz, MD, MS

Asthma complicates up to 8% of pregnancies, and nasal symptoms occur in

of asthma and rhinitis medications during pregnancy, a topic of prime interest to

Michael Schatz, MD, MS

Respiratory Physiologic Changes in Pregnancy

Effect of pregnancy on ventilation and gas exchange

Resting minute ventilation increases during pregnancy [7–9]. This is primarily

Physiologic dyspnea of pregnancy

The increase in minute ventilation that accompanies pregnancy often is per-

(change in oxygen consumption per change in work load) is unchanged [36];

Lung and chest wall mechanics in pregnancy

Forced expiratory spirometry is useful to follow patients who have asthma.

Sleep and pregnancy

Sleep disturbances are common during pregnancy as the result of bio-

Effect of pregnancy on chronic pulmonary diseases

Sarcoidosis is the classic example of a disease that tends to stabilize or im-

Pulmonary embolic disease in pregnancy

The two leading causes of unexpected maternal deaths are thromboembolic

Safety of Asthma and Allergy Medications

E-mail address: cchambers@ucsd.edu

Medications used for the treatment of asthma in pregnancy

Published studies of pregnancy outcome in asthmatic women who were

of spontaneous abortion among 824 asthmatic women and 678 nonasthmatic

Selected studies of pregnancy outcomes associated with theophylline use are

pregnant control women, Stenius-Aarniala and colleagues [9] found no signifi-

Selected studies that addressed the effects of short-acting bronchodilators on

from the Collaborative Perinatal Project showed no significant increased risk

The MFMU study included 77 salmeterol-exposed subjects; outcomes were

In contrast to generally reassuring data about most older asthma medications,

The second study, which was published in 1998 by Rodriguez-Pinilla and

Limited recent data are available on the safety of cromolyn in pregnancy. In

Medications used for the treatment of rhinitis in pregnancy

Among the decongestants, phenylephrine has been associated with an in-

Intranasal allergy medications

In addition to oral decongestants, Werler and colleagues [37] examined the

[1] Lenz W. Thalidomide and congenital abnormalities. Lancet 1962;1:271 – 2.

The Epidemiology of Asthma During

Asthma is reported to be the most common obstructive pulmonary disease of

Prevalence of asthma during pregnancy in the United States

Assessment of pregnancy and asthma

Estimates of asthma prevalence

the past 12 months, did anyone in the family have

Trends in asthma prevalence over time

18–24 670,658 4.7 3.5–5.9 262,020 1.8 0.9–2.7 — —

18–24 5.4 5.0–5.9 1.7 1.4–2.0 5.4 3.9–7.5 1.9 1.2–3.0

Estimates of asthma control during pregnancy

Table 4 also shows that the estimated annual prevalence of self-reported

unmarried, of lower income status, of Hispanic or Latino heritage, or live in the

Prevalence of asthma during pregnancy internationally

We assessed recent international reports of asthma in pregnancy. An electronic

continuing, or having had an attack

Box 1. Summary: asthma prevalence

Asthma was estimated to affect between 157,648 and 209,396

How valid are survey data on asthma prevalence?

Survey prevalence data are heavily dependent on the diagnosis of asthma by a

Prevalence of asthma is estimated from national surveys in which women are

Some investigators also identified gender differences in asthma diagnosis in

Box 2. Summary: asthma diagnosis

Symptoms (wheeze, chest tightness, persistent cough) are