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OBSTETRICS
In utero beta 2 adrenergic agonist exposure and adverse
neurophysiologic and behavioral outcomes
Frank R. Witter, MD; Andrew W. Zimmerman, MD; James P. Reichmann, MBA; Susan L. Connors, MD
Beta 2 adrenergic agonist drugs as a
class are used widely in obstetrics as
both tocolytics and bronchodilators.
This article will correlate the basic science
and clinical data to illustrate that,
when given prenatally, they can act as
functional and behavioral teratogens in
that they can alter permanently the balance
of sympathetic and parasympathetic
tone in the individual after exposure
in utero.
Animal studies will be presented to
support the concept that, in humans,
prenatal exposure to continuous high
doses of beta 2 adrenergic agonists can
dysregulate signaling from the beta 2 adrenergic
receptor (B2AR) permanently.
The association between sympathetic overactivity and disease will be illustrated,
and the association between in
utero exposure to beta 2 adrenergic agonists
in humans and the later development
of these conditions or their precursors
will be demonstrated. Additionally,
data to support a genetic predisposition
to the teratogenic effect of beta 2 adrenergic
agonists will be presented.
The implications for safe practice in
obstetrics will be discussed in light of the
teratogenic risk that is posed by beta 2
adrenergic agonists.
Basic science data that support
receptor sensitization
Terbutaline and similar drugs stimulate
the B2AR, which is part of the catecholamine
system of neurotransmitters. Cell
signaling that is associated with B2AR
stimulation results from the binding of
the ligands norepinephrine in the central
nervous system (CNS) and norepinephrine
and epinephrine in peripheral
tissues. The B2AR is expressed on mammalian
oocytes and preimplantation embryos.
1 Beta adrenergic receptors are expressed
widely in mammalian tissues,
which includes the brain during gestation.
2 In addition to coupling with the
stimulatory G protein to activate adenylyl
cyclase, generating cyclic adenosine
monophosphate and protein kinase A,
and increasing intracellular calcium as
second messengers, activation of the
B2AR also stimulates or inhibits mitogen-
activated protein kinases, which
regulate basic cell processes such as
growth, differentiation, apoptosis, and
migration.3,4 Early in fetal life, B2AR
stimulation coupled with cyclic adenosine
monophosphate generation provides
signals for growth and later promotes
important mechanisms, such as
axonal outgrowth in neural cells and differentiation
in diverse tissues.5-7
B2AR signaling is regulated during
postnatal life by desensitization (decreased
signaling) and down-regulation
(decreased numbers of receptors on the
cell surface). Both processes terminate
cell signaling if excessive input occurs
and are essential homeostatic mechanisms
that protect the cell from overstimulation
and metabolic acidosis. Animal
studies have shown that these
protective regulatory mechanisms for
B2AR signaling are not intrinsic properties
of cells but are acquired during prenatal
development. Fetal and newborn
tissues are not only resistant to B2AR desensitization
but actually show the opposite:
agonist stimulation of the fetal
receptor enhances net physiologic responses,
instead of producing desensiti-
From the Division of Maternal-Fetal
Medicine, Department of Gynecology and
Obstetrics (Dr Witter), Department of
Neurology and Developmental Medicine,
Kennedy Krieger Institute (Drs Zimmerman
and Connors) and Departments of
Neurology, Psychiatry, and Pediatrics (Dr
Zimmerman), Johns Hopkins University
School of Medicine, Baltimore, MD;
Department of Epidemiology, Johns
Hopkins University Bloomberg School of
Public Health, Baltimore,MD(Dr
Zimmerman); American Home Patient,
Brentwood, TN (Mr Reichmann);
LADDERS Clinic of Mass General Hospital
and Harvard Medical School, Boston,MA
(Dr Connors).
Received June 9, 2009; revised June 18, 2009;
accepted July 6, 2009.
Reprints not available from the authors.
Authorship and contribution to the article is
limited to the 4 authors indicated. There was
no outside funding or technical assistance with
the production of this article.
0002-9378/free
© 2009 Mosby, Inc. All rights reserved.
doi: 10.1016/j.ajog.2009.07.010
For Editors’ Commentary,
see Table of Contents
Beta 2 adrenergic receptor overstimulation during critical periods of prenatal development
can induce a permanent shift in the balance of sympathetic-to-parasympathetic tone. This
is a biologically plausible mechanism whereby beta 2 adrenergic agonists can induce
functional and behavioral teratogenesis, which explains their association with increases in
autism spectrum disorders, psychiatric disorders, poor cognitive, motor function and
school performance, and changes in blood pressure in the offspring. The use of beta 2
adrenergic agonists should be limited to proven indications when alternate drugs are
ineffective or unavailable; the risks of untreated disease to the mother and fetus are greater
than the risk of the beta 2 adrenergic agonist.
Key words: asthma, autism spectrum disorder, beta 2 adrenergic agonist, preterm
labor, ritodrine, terbutaline
www.AJOG.org Obstetrics Reviews
DECEMBER 2009 American Journal of Obstetrics & Gynecology 553
zation, as in adult tissues.8,9 The beta 2
agonist terbutaline crosses the placenta
and blood brain barrier and stimulates
B2ARs in all tissues of the fetus.2,10,11
Thus, exposures during pregnancy that
increase B2AR signaling or overstimulate
the receptor could have widespread
effects in light of the function of these
receptors during pre- and postnatal life.
The severity of effects depends on the
dose and duration of the exposure and,
most importantly, the stage of development
of specific brain regions and organs
during the time of insult.12,13
Rodent studies have shown that daily
subcutaneous injections of terbutaline
during postnatal days 2-5 result in abnormalities
in brain development and
behavior, compared with control rats.
Differences include changes in microarchitecture
in the cerebellum, hippocampus,
and cortex in juvenile rats (postnatal
day 30), functional differences in cell
signaling in juvenile and adolescent
(postnatal day 45) and adult rats (postnatal
day 60), behavioral changes in juvenile
rats, and neuroinflammation of
the brain in juvenile rats. These findings
are similar to those found in autism.
8,12-16 The amount of terbutaline
that is used (10 mg/kg) leads to robust
beta adrenergic receptor stimulation in
the neonatal rat.8 The dosage of terbutaline
in human pregnancy is 0.5-2 mg/kg/
d17,18; however, because the drug has a
much shorter half-life in the rat,19 the
dose that was used by the researchers
cited earlier was proportionately
higher.14 The 4-day duration for terbutaline
administration (postnatal days
2-5) is equivalent to 3-4 weeks in human
pregnancy.20,21 This early postnatal period
in the rat correlates with the mid-tolate
second and early third trimester in
human gestation,20,21 which are periods
during which pregnant women may be
treated with a B2AR agonist for preterm
labor. Previous research in rodents has
also shown that the period of postnatal
days 2-5 is a critical window in CNS and
tissue development. Administration of
terbutaline during the later period of
postnatal days 11-14 leads to fewer and
different abnormalities than those induced
by the early treatment.8
Data that support sympathetic
overactivity in selected diseases
Overactivity of the sympathetic nervous
system has been implicated in the cause
of certain disease states and contributes
to abnormal function in others. Increased
catecholamine levels are part of
the disease process in congestive heart
failure and cause chronic stimulation of
beta adrenergic receptors, which results
in tachycardia and increased contractility.
22,23 This overstimulation leads to receptor
desensitization, abnormal downstream
cellular signaling, and maladaptation
that eventually results in myocyte
hypertrophy, ventricular chamber enlargement,
and fibrosis. By decreasing beta
adrenergic receptor stimulation, beta
blockers have become part of the basic
treatment for this condition.
Hypertension, like congestive heart
failure, often is treated with beta adrenergic
receptor antagonists, although
overstimulation of beta receptors is not
thought to be the basis for this condition.
24 The exact mechanism for beta
blockers antihypertensive effects is unknown
but is thought to be due to several
modes of action, which include antagonism
of beta 1 adrenergic receptors in the
renal vascular bed. Stimulation of these
receptors normally produces renin;
blocking these receptors decreases renin
levels and conversion of renin to angiotensin
II, which is a potent vasoconstrictor.
Other mechanisms may involve
blocking beta adrenergic receptors that
control sympathetic outflow in the CNS
and changes in arterial baroceptor
sensitivity.
Ming et al25 measured baseline cardiovascular
autonomic function in children
with autism (ages, 4-14) and in agematched
healthy control subjects. They
found that measures of parasympathetic
activity, cardiac vagal tone, and cardiac
sensitivity to baroreflex were significantly
lower in children with autism,
compared with control subjects, and
were associated with significant elevations
in indices of sympathetic tone:
heart rate, mean arterial blood pressure,
and diastolic blood pressure. Low levels
of cardiac vagal tone and cardiac sensitivity
to baroreflex suggest impaired cardiac
parasympathetic activity, with unrestrained
and hyperactivity of the
sympathetic nervous system.
Rodent work has shown that overstimulation
of the B2AR by terbutaline
during postnatal days 2-5 results in effects
that can be related indirectly to
sympathetic hyperactivity, as in the
study of Ming et al.25 Acetylcholine receptors
that are found in the cardiovascular
system that normally act to balance
the catecholamine system are decreased
in number and function in the heart after
neonatal terbutaline administration.8,26
This would lead to a loss of parasympathetic
balance and overactivity in sympathetic
responses.
Human data that support poor
neurophysiologic and behavioral
outcomes after beta 2 adrenergic
agonist exposure in utero
The association of poor neurophysiologic
and behavioral outcomes in children
who are exposed in utero is seen
with _1 agent of this class. Terbutaline
has been associated with delayed development
of expressive language.27 Continuous
terbutaline treatment for _2
weeks in the treatment of preterm labor
was associated with an increased concordance
of autism spectrum disorders in
dizygotic twins.28 In utero exposure to
terbutaline by intravenous use for tocolysis
or aerosol for asthma has also been
correlated with autism.29 A reported association
of maternal asthma and autism
spectrum disorders in the offspring
might be explained by treatment with
beta 2 adrenergic agonists for treatment
of asthma during pregnancy.30 A recent
case control study that involved 398 children
with an autism spectrum disorder
diagnosis and 110 normal control children
who were matched for sex, birth
year, and birth hospital found that beta 2
adrenergic agonist exposure in the first
and second trimester may be associated
with a modest increase in the risk of having
a child with an autism spectrum disorder
(L.A. Croen, personal communication,
2009). In this study, albuterol was
the most frequently used beta 2 adrenergic
agonist in the first and second trimester,
which indicates that asthma treat-
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554 American Journal of Obstetrics & Gynecology DECEMBER 2009
ment may have been the reason for beta 2
adrenergic agonist use.
Increased psychiatric disorders together
with poorer cognitive and motor
performance have been seen in the largest
long-term prospective study of infants
who are born after in utero exposure
to beta 2 adrenergic agonists.31 In
this study, the agent was intravenous
fenoterol, followed by unspecified oral
beta 2 adrenergic agonists. Only those
children who were exposed to a longer
duration of therapy were affected
significantly.
Ritodrine exposure for tocolysis has
also been associated with poorer school
performance, compared with matched
control subjects.32 It is remarkable that
this finding in school performance occurred
despite the lack of difference
between the groups in developmental
delay, neurologic abnormalities, or behavioral
differences.
Alvarez et al33 found a hypertensive effect
in adolescents (ages, 13-16 years)
who had been exposed in utero to the
beta sympathomimetic ritodrine and
who were full-term births, compared
with control subjects without the exposure.
Heart rates and blood pressures
were measured for 48 hours with the use
of an ambulatory monitor. Teenagers
who had been exposed to ritodrine in
utero had higher heart rates, wider
ranges in systolic blood pressure, and
higher diastolic blood pressure than did
control subjects.
Not all follow-up studies of patients
who were exposed to beta 2 adrenergic
agonists have shown these adverse outcomes.
Other studies with isoxuprine34
and ritodrine35,36 have shown no adverse
effects when compared with control subjects.
One case series that included no
control subjects also showed no adverse
long-term sequellae at 2 years of age after
in utero exposure to terbutaline.37 The
ritodrine studies began with approximately
2 days of parenteral therapy followed
by oral treatment.35,36 Given ritodrine’s
relatively short half-life and the
listed oral dosing, it is likely that continuous
exposure at a sufficient level to
cause functional teratogenesis was not
present in the studies. Likewise, the isoxsuprine
study involved only short-term
exposure, and it is likely that insignificant
exposure occurred and may have
avoided functional teratogenisis.34 The
terbutaline study lacked control subjects
and involved the initiation of therapy between
27 and 36 weeks of gestation.37
Thirty-one percent of the patients in this
study started terbutaline therapy between
35 and 36 weeks of gestation. Animal
studies would suggest that the midto-
late third trimester may be too late to
see a major effect from beta 2 adrenergic
agonists. Thus, a sizable proportion of
the exposed subjects in this study might
not have been at the gestational age of
maximal risk.
Genetic predisposition
Single nucleotide substitutions or polymorphisms
of the B2AR gene have been
described. Three of these (Gly16, Glu27,
and Ile164) code for changes in the receptor’s
amino acid sequence that lead to
physiologic differences in receptor signaling.
Stimulation of the Gly16 and
Glu27 receptors in vivo results in decreased
desensitization and down-regulation
and is associated with enhanced
signaling,38,39 compared with the wildtype
variants Arg16 and Gln27. The
Ile164 polymorphism results in reduced
affinity for ligand binding and lower levels
of second messenger formation.40
Polymorphisms of the B2AR gene
have been associated with susceptibility
to and prognosis in diverse diseases and
conditions that include medication response
in asthma,41 occurrence of type 2
diabetes mellitus,42 outcome in congestive
heart failure,43,44 Grave’s disease,45
myasthenia gravis,46 rheumatoid arthritis,
47 obesity,48 and psychologic coping.
49 Connors et al28 found an increase
in the more active polymorphisms of the
B2AR in twins with autism spectrum disorders,
and Cheslack-Postava et al50
found an increased prevalence and
transmission of these polymorphisms in
singleton autism births. Thus, genetic
polymorphisms can change the physiologic
condition of receptor function and
contribute to predispositions for several
disease states. Considering the importance
of the B2AR in normal brain and
organ development, it is likely that polymorphisms
that increase or decrease signaling
are genetic risk factors for abnormal
brain development during gestation,
in a similar way as they are linked to disease
in other organs. The presence of
polymorphisms that are associated with
enhanced signaling would then become
a susceptibility factor for exposures to
sympathomimetic drugs and may be a
factor in defining the “population at
risk” for later neurodevelopmental disorders
in children after exposure to beta
2 adrenergic agonists during gestation.
Implications for clinical practice
Bronchodilator therapy with beta 2 adrenergic
agonists remains a mainstay of
asthma treatment. Data from 1995-1999
linked the diagnosis of maternal asthma
to autism spectrum disorders.30 In 2005,
the updated National Asthma Education
Report of the working group on asthma
and pregnancy removed oral beta 2 adrenergic
agonists from the recommended
pharmacologic therapy for
asthma during pregnancy.51 Inhaled
beta 2 adrenergic agonists remain a part
of the medically indicated therapy for
this potentially life-threatening condition.
Injected beta 2 adrenergic agonists
are not recommended because there is
no proven benefit of systemic therapy
over inhalation therapy.51
Albuterol is the preferred short-acting
inhaled beta 2 adrenergic agonist because
of the extensive data on the safety
of this agent during pregnancy.51 It
should be used for quick relief of symptoms
and to treat mild intermittent
asthma. Care should be taken to avoid
excessive treatment in light of the association
between albuterol exposure in the
first and second trimesters and a modest
increase in autism spectrum disorders in
the child (L.A. Croen, personal communication,
2009).
In patients with mild intermittent
asthma with symptoms on _2 days per
week and _2 nights per month, the
working group recommends low-dose
inhaled corticosteroid therapy as the
preferred treatment during pregnancy.51
Because of more data being available on
its use in pregnancy, budesonide was the
recommended inhaled steroid. Lowdose
budesonide inhalation is recommended
in the range of 200-600_g daily.
www.AJOG.org Obstetrics Reviews
DECEMBER 2009 American Journal of Obstetrics & Gynecology 555
If the patient’s symptoms occur daily
or _1 night a week, her asthma has progressed
to moderate persistent asthma.
For this severity, the working group has 2
alternate preferred treatments.51 To
avoid increased beta 2 adrenergic agonist
exposure, the treatment with mediumdose
inhaled corticosteroids should be
selected because the 2 regimens are
equally preferred. This would correspond
to 600-1200 _g of budesonide.
With the use of moderate-dose inhaled
corticosteroid, an additional benefit of
avoiding increased polypharmacy would
be achieved.
If the pregnant asthmatic woman has
continued daily symptoms and frequent
night symptoms, she has severe persistent
asthma. For these patients, the
working group recommends high-dose
inhaled corticosteroids and a long-acting
inhaled beta 2 adrenergic agonist.51 This
would correspond to an inhaled dose of
budesonide of_1200_g daily. There are
2 long-acting beta 2 adrenergic agonists
available: salmeterol and formoterol.
The working group recommends salmeterol
as the preferred long-acting beta 2
adrenergic agonist for pregnancy because
there was greater experience in
pregnancy with this agent.51 Long-acting
beta 2 adrenergic agonist use can lead to
tachyphylaxis for the B2ARs and is associated
with an increased risk of serious
adverse events and of asthma-related
deaths.52-54 Whether this increase in
asthma-related death is attenuated by
the concomitant use of inhaled steroid
cannot be determined from the available
data.54
An alternate, but not preferred, treatment
for severe persistent asthma is
high-dose inhaled corticosteroid therapy
plus sustained release theophylline to a
serum concentration of 5-12 _g/mL.51
Salmeterol has been shown to be more
effective in this group of asthmatic patients
when compared with sustained release
theophylline as maintenance therapy.
55 Although salmeterol plasma levels
after inhalation are low to nondetectable,
56 to avoid the risk of salmeterol, a
trial of theophylline may be worthwhile
in pregnant asthmatic women.
Beta 2 adrenergic agonist
use as a tocolytic
Short-term use of beta 2
adrenergic agonists
Beta 2 adrenergic agonists have been
used extensively to treat preterm labor
either intravenously or intramuscularly.
Ritodrine is the only agent of this class to
be approved by the Food and Drug Administration
for this indication. As such,
sales data were used by Leveno et al57
in 1990 to estimate that, although
_100,000 women were treated for preterm
labor with this agent annually,
there was no evidence that it had any impact
on low birthweight in the United
States.
Although many beta 2 adrenergic agonists
have been used to treat preterm labor
worldwide, only terbutaline is currently
in use in the United States. Headto-
head comparisons of ritodrine and
terbutaline have failed to show any difference
in efficacy58,59; this is true of
other beta 2 adrenergic agonists as well.60
The evidence for efficacy can be treated
interchangeably with these agents.
In the evaluation of agents for treatment
of preterm labor, it is important to
note that there is a demonstrated placebo
effect of approximately 20-50%.60
Therefore, only randomized placebo
controlled trials will give the most reliable
assessment of these agents. Ritodrine,
which is the most studied of these
agents, has not been shown to affect significantly
gestational age, birthweight,
incidence of low birthweight, or measures
of neonatal morbidity.61-64 It did
result in prolongation of gestation for 48
hours, which could allow for administration
of steroids to induce fetal lung
maturation.62,65
The American College of Obstetricians
and Gynecologists (ACOG) recommends
the use of tocolysis, including
beta 2 adrenergic agonists to allow steroid
administration to improve lung
maturation or to allow transport to a tertiary
care facility.66 Based on current
available data, short-term use for 48-72
hours should not pose an undue risk of
the induction of functional or behavioral
teratogenic effects from beta 2 adrenergic
agonists, and they may remain
among the agents that are available to clinicians
for this indication, if other tocolytic
agents pose a greater risk for the individual
patient. However, there may be
a subpopulation of mothers and fetuses
at increased risk because of the presence
of genetic polymorphisms of the B2AR
or other unknown factors. Further studies
are needed to establish the safety of
short-term exposure to these drugs.
Subcutaneous maintenance therapy
Based on case series, terbutaline that is
given by continuous subcutaneous
pump has gained popularity as a maintenance
therapy after threatened preterm
labor to prevent preterm birth. However,
because of the 20-50% placebo effect
that is seen in threatening preterm
labor,60 these reports are insufficient to
assess this therapy, and controlled trials
are required. There were 2 placebo controlled
trials of this therapy, both of
which failed to show any benefit.67,68
Both ACOG and Cochrane reviews of
subcutaneous terbutaline pump maintenance
tocolytic therapy agree that it is
ineffective.64,69 The Agency for Healthcare
Research and Quality assessed beta 2
adrenergic agonists as “high” in probability
of maternal risk, ineffective when
used for maintenance tocolysis, and advised
against any further research on
maintenance tocolytic use.70
In a large case series,71 cardiopulmonary
problems were seen in 0.54% of the
patients, and pulmonary edema was seen
in 0.32% of the patients. There are additional
reported cases of pulmonary
edema,72 terbutaline hepatitis,73 and
sudden death.74 The incidence of abnormal
glucose tolerance has been reported
in 1 case series,75 but not in another.76
However, in the study that did not report
an increase in glucose intolerance, the
need for insulin therapy was increased in
those patients receiving terbutaline.76
Adverse events with subcutaneous terbutaline
pump therapy are not limited to
the mother. Neonatal myocardial necrosis
also has been reported with long-term
subcutaneous terbutaline pump therapy.
77 Continuous exposure to terbutaline
for tocolysis by any route for at least 2
weeks has been associated with autism
spectrum disorders in the child.28
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556 American Journal of Obstetrics & Gynecology DECEMBER 2009
Because prolonged subcutaneous beta
2 adrenergic agonist treatment is not effective66
and has significant maternal
and fetal risks, its use should be abandoned.
There is no setting in which the
benefit has been shown to justify the risk.
Unfortunately, it continues to be prescribed
by 2% of maternal-fetal medicine
specialists.78 The actual rate of prescribing
may be higher because 31% of
maternal-fetal medicine specialists who
would not recommend maintenance tocolysis
will prescribe maintenance tocolysis
on patient request, but data are not
available about how often this occurs
and what maintenance tocolytics are
prescribed.78
Oral maintenance therapy
Although an early small placebo controlled
trial favored oral terbutaline over
placebo,79 a larger trial later showed a
lack of efficacy.80 The Cochrane Collaborative
Reviews recently reviewed 11
randomized controlled trials of oral beta
2 adrenergic agonists and concluded that
the evidence did not support their use for
maintenance therapy after treatment of
threatened preterm labor.81 An ACOG66
practice bulletin also assesses prolonged
oral treatment as not effective. Studies
cited earlier show that adverse functional
abnormalities in rats were at doses that
were designed to mimic oral or subcutaneous
administration of terbutaline.
8,17,18 Because there is no potential
benefit from this therapy and because of
potential risk based on animal data, the
use of oral maintenance therapy for
threatened preterm labor should be
abandoned. Unfortunately, it continues
to be prescribed by 4% of maternal-fetal
medicine specialists.78 As noted earlier
for subcutaneous therapy, the actual rate
of oral tocolysis may be higher than reported;
however, data are not available
for the frequency, types, or duration of
exposure.78
Acute treatment for fetal distress
Beta 2 adrenergic agonists, primarily terbutaline,
have been advocated for use in
intrauterine resuscitation for nonreassuring
fetal heart rate patterns and for
episodes of uterine tachysystole. Intravenous
ritodrine that is given continuously
during the second stage of labor abolished
the progressive fetal respiratory acidosis
that is seen during normal labor in
1 double-blind controlled trial.82 Single
bolus injections of 250 _g of terbutaline
were reported in case series to improve
fetal pH in cases of nonreassuring fetal
status that included bradycardia that
lasted for 2 minutes; fetal pH was unresponsive
to other methods.83,84 Additionally,
this single injection therapy has
been shown to be effective in temporary
inhibition of uterine activity at term.85 A
controlled trial confirmed these findings.
86 Based on these data, the use of
intravenous boluses of 250 _g of terbutaline
has been established as the standard
temporizing treatment for a nonreassuring
status in utero, especially when
associated with uterine tachysystoly.87
Terbutaline crosses the placenta after a
single intravenous bolus of 250 _g and
reaches a maximum fetal umbilical
plasma concentration of one-half of the
maximum maternal plasma concentration
and ranges from 0.75-3.46_g/L.10 A
single dose of this magnitude is unlikely
to result in injury to the fetal nervous system
because of the short duration of exposure.
Therefore, the balance of risk
and benefit for this form of beta 2 adrenergic
agonist therapy is in favor of its
continued use in clinical practice.
Conclusion
The permanent shift in the balance of
sympathetic-to-parasympathetic tone,
as a result of B2AR overstimulation during
critical periods of prenatal development,
is a biologically plausible mechanism
whereby beta 2 adrenergic agonists
can induce functional and behavioral
teratogenesis. Although the exact dose
and duration of exposure to achieve
these results is not yet established, currently
available data concerning increased
risk for autism in the offspring
suggest that the duration is likely to be
_2 weeks of continuous high-dose exposure.
The period of maximum teratogenic
risk is likely related to the time of
maximal brain development from the
mid-to-late second trimester through at
least the early third trimester. In addition
to autism spectrum disorders, conditions
that may be related to this teratogenesis
include increased psychiatric disorders,
poor cognitive and motor
function and school performance, and
changes in blood pressure.
Given the risk of long-term neurophysiologic
and behavioral impairment,
the use of beta 2 adrenergic agonists
should be limited to proven indications
when alternate drugs are ineffective or
unavailable and when the risks of the untreated
disease to the mother and fetus
are greater than the risk of the beta 2 adrenergic
agonist. Treatment duration
should be as short as clinically feasible.
Further ongoing surveillance of the use
of these agents in pregnancy is needed to
refine the parameters for their safe use in
pregnancy. Future pharmacogenetics research
is also needed to better characterize
the highest risk group for teratogenesis
from these agents. f
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