Medications in Pregnancy and Lactation Clinical Expert Series

Transcription

Medications in Pregnancy and Lactation Clinical Expert Series
Clinical Expert Series
Continuing medical education is available online at www.greenjournal.org
Medications in Pregnancy and Lactation
Part 2. Drugs With Minimal or Unknown Human Teratogenic Effect
Catalin S. Buhimschi,
MD,
and Carl P. Weiner,
MD, MBA
This is the second of a two-part series on the use of medication during pregnancy and lactation.
Pregnancy risk factors together with an increased incidence of chronic diseases and the rise in mean
maternal age predict an increase in medication use during gestation. However, as highlighted in the
first installment of this series, relatively few medications have specifically been tested for safety and
efficacy during pregnancy, and, therefore, responses to those inquiries can be uninformed and
inaccurate. Whereas the first installment provided new insight into the nature of medications with
known human teratogenic effects, this part concentrates on drugs with minimal or no known human
teratogenic effect. It is important that clinicians become familiar with all of the aspects of the drugs
they prescribe, in addition to the controversies surrounding them, through consultation with
maternal–fetal medicine specialists and through references and Web sites providing up-to-date
information in an effort to promote safer prescribing practices.
(Obstet Gynecol 2009;113:417–32)
P
atients commonly inquire during prenatal care as
to the effects of certain medications on their
pregnancies. Unfortunately, clinicians typically have
insufficient information about the risks and benefits of
all the medications they prescribe. To help overcome
this obstacle, the U.S. Food and Drug Administration
introduced a classification of medications associated
with fetal risks during pregnancy (Table 1). This system
suffers many weaknesses, however, which were reviewed in the first part of this series. Part I provides new
From the Department of Obstetrics, Gynecology and Reproductive Science, Yale
University School of Medicine, New Haven, Connecticut; and Department of
Obstetrics and Gynecology, University of Kansas School of Medicine, Kansas
City, Kansas.
The authors thank Kelly Horvath, MA, for her assistance with the writing and
editing of the manuscript.
Continuing medical education is available online at http://links.lww.com/A677.
Corresponding author: Catalin S. Buhimschi, MD, Director, Perinatal Research, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale
University School of Medicine, 333 Cedar Street, LLCI 804, New Haven, CT
06520; e-mail: [email protected].
Financial Disclosure
The authors did not report any potential conflicts of interest.
© 2009 by The American College of Obstetricians and Gynecologists. Published
by Lippincott Williams & Wilkins.
ISSN: 0029-7844/09
VOL. 113, NO. 2, PART 1, FEBRUARY 2009
insight into the nature of medications with known
human teratogenic effects (Category X). This second
installment concentrates on drugs with minimal or unknown human teratogenic effects. Table 2 lists some of
the most common medications (in alphabetical order)
with minimal or unknown human teratogenic effects.
Categories A and B generally are considered safe in
humans as approved by the U.S. Food and Drug
Administration. Category C medications have not been
definitively shown to be harmful to human fetuses, but
reasons exist to be cautious when prescribing them.
Category D drugs are those with evidence of human
fetal risk based on well-controlled human studies, but
the benefits of treatment outweigh the risks.
Table 3 provides a summary of commonly prescribed drugs with minimal or unknown teratogenic
effect. This information is based on the best available
evidence at the time this report was written. The
research strategy included computerized bibliographic searches (generic and dominant trade names)
of MEDLINE (1966 –2008), PubMed (1966 –2008),
and references of published articles. Meta-analysis
studies were included only if the guidelines of the
Meta-analysis of Observational Studies in Epidemiology Group were appropriately applied. The Ameri-
OBSTETRICS & GYNECOLOGY
417
Table 1. United States Food and Drug Administration Drug Classification System
FDA
Category*
Pregnancy Category Definition
A
Controlled studies showed no risk to humans. Adequate, well-controlled studies in pregnant women have not
shown an increased risk of fetal abnormalities.
B
No evidence of risk in humans.
Animal studies have revealed no evidence of harm to the fetus. However, there are no adequate and wellcontrolled studies in pregnant women.
or
Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have
failed to demonstrate a risk to the fetus.
C
Risks cannot be ruled out in humans.
Animal studies have shown an adverse effect, and there are no adequate and well-controlled studies in pregnant women.
or
No animal studies have been conducted, and there are no adequate and well-controlled studies in pregnant women.
D
Clear evidence of risk in humans.
Studies, adequate well-controlled or observational, in pregnant women have demonstrated a risk to the fetus.
However, the benefits of therapy may outweigh the potential risk.
X
Drugs contraindicated in human pregnancy.
Studies, adequate well-controlled or observational, in animals or pregnant women have demonstrated positive
evidence of fetal abnormalities. The use of the product is contraindicated in women who are or may become
pregnant.
FDA, U.S. Food and Drug Administration.
* Please verify the FDA categorization for each drug.
can College of Obstetricians and Gynecologists’
Committee Opinion and Practice Bulletins also were
used. For clinical relevance, trade names for the
commonly used drugs also are included.
Table 2. Commonly Prescribed Drugs With
Minimal or Unknown Teratogenicity*
FDA
Classification†
Drug
Analgesics
Aspirin, acetaminophen, ibuprofen
Antibiotics
Penicillin-G, tetracyclines, ciprofloxacin,
metronidazole, nitrofurantoin,
azithromycin
Anticholinergics
Albuterol, atropine, dimenhydrinate
Antihypertensive agents
Methyldopa, hydralazine, labetalol,
propranolol
Antihistamines
Cetirizine, diphenhydramine
Antivirals
Acyclovir
Corticosteroids
Prednisone, betamethasone,
dexamethasone
B–D (see class)
B–D (see class)
B–C (see class)
B–C (see class)
B
B
B
FDA, U.S. Food and Drug Administration.
* Drugs or drug groups with minimal or unknown human teratogenic effect (see Table 1 for an explanation of the safety
categories).
†
Please verify the FDA categorization for each drug.
418
Buhimschi and Weiner
CONCLUSION
Whether or not to prescribe a drug for a pregnant or
breast-feeding woman is a decision that must be made
in consideration of many factors, including but not
limited to, gestational age of the embryo or fetus,
route of drug administration, absorption rate of the
drug, whether the drug crosses the placenta or is
excreted in breast milk, the necessary effective dose of
the drug, molecular weight of the drug, whether
monotherapy is sufficient or if multiple drugs are
necessary to be effective, and even the mother’s
genotype. Potential harm to the fetus or nursing infant
is paramount among these factors. Large registries
and case-control studies with longer follow-up periods
are necessary before concluding definitively whether
a medication is safe. Equally important is assessment
of the potential harm to the mother that withholding
a drug can cause. The decision, then, typically comes
down to, “Does the benefit of the drug outweigh its
risks?”
However, accurately weighing benefit against risk
requires a thorough understanding of those benefits
and risks. Current methods to assess and classify drug
risk are spotty at best. Pharmaceutical companies gain
approval to market drugs before follow-up studies
have been conducted on their long-term effects.
Moreover, pregnant and breast-feeding women are
not appropriate test participants precisely because of
the risk of drug teratogenicity. This investigation scruti-
Medications in Pregnancy and Lactation
OBSTETRICS & GYNECOLOGY
Table 3. Considerations for Drugs with Minimal or Unknown Teratogenic Effect
Drug
Analgesics
Whole category (aspirin,
acetaminophen,
ibuprofen)
Aspirin
Maternal Considerations
Fetal Considerations
Breast-Feeding
Considerations
Y Lack of consensus regarding
management of women who
have both antiphospholipid
antibodies and a history of
recurrent pregnancy loss reflects
the wide range of clinical
manifestations.
Y A large cohort study concluded
the antenatal use of
nonsteroidal antiinflammatory
drugs such as ibuprofen,
naproxen, and aspirin but not
acetaminophen increased the
risk of spontaneous abortion.1
—
—
Y Collectively, large trials
Y Crosses human placenta.
Y Compatible with
demonstrate low-dose aspirin’s Y Associated with an
breast-feeding.16,17,18
Y Some experts suggest
relative safety during
increased risk of fetal
breast-feeding mothers use
pregnancy and generally
vascular disruptions,
the lowest effective dose
positive effects on reproductive
particularly gastroschisis,
and for the shortest
outcomes.
small intestine atresia, and
duration taken after
Y Understanding the mechanism
possibly premature closure
feeding.
of action still incomplete.2,3
of the ductus
Y Gastrointestinal lesions, renal or
Y Women requiring high
arteriosus.6,14,15
Y Should be avoided in the
hepatic dysfunction, asthma,
doses such as that used for
first trimester to prevent
hypoprothrombinemia,
arthritis or rheumatic
gastroschisis.15
tachypnea, hyperthermia, and
fever should avoid breastlethargy are the most significant
feeding because neonatal
risks.4
salicylate levels may reach
Y Has small but significant effect on
toxic levels.
reducing the rate of preterm
delivery but not perinatal death.5
Y Used to improve pregnancy
outcomes in women who have
both antiphospholipid
antibodies and a history of
recurrent pregnancy loss:
– theorized that aspirin
interferes with the potential
of these antibodies to
compromise implantation and
placental angiogenesis.6,7
– aspirin plus heparin remains the
most efficacious treatment8 for
women with a history of at least
two spontaneous miscarriages
or one intrauterine fetal death
without apparent cause other
than inherited or acquired
thrombophilias.9
– however, in a 2002 randomized
trial, a high success rate was
achieved when low-dose aspirin
alone was used for the
treatment of antiphospholipid
syndrome; the addition of low
molecular weight heparin did
not improve outcome.10
(continued)
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Table 3. Considerations for Drugs with Minimal or Unknown Teratogenic Effect (continued)
Drug
Maternal Considerations
Analgesics
Aspirin (continued)
Acetaminophen
(Tylenol, Apacet)
Fetal Considerations
Breast-Feeding
Considerations
Y Prescribed to reduce the risk of
maternal thrombosis:
– alone is not sufficient to
prevent thrombosis.
– not without risk: may
contribute to maternal
bleeding due to its effect on
platelet cyclooxygenase
enzymes, and clinicians often
avoid recommending it
during the third trimester.
Y Use for prevention of
preeclampsia also remains
controversial:
– several meta-analyses suggest
a modest reduction in
preeclampsia and intrauterine
growth restriction.11,12
– but most recent meta-analysis
indicates that antiplatelet
agents are associated with
moderate but consistent
reductions in the relative risk
of preeclampsia.13
Y One of the most widely used
medications during pregnancy.
Y Most common maternal
problems relate to chronic
abuse and overdose:
– damage appears secondary to
free radical toxicity with the
consumption of glutathione
during the acetaminophen
metabolism.
– N-acetylcysteine is the
treatment of choice for an
acute overdose.19
Y Used to treat the fever of Y Compatible with
chorioamnionitis during
breast-feeding.16,17,18
labor and associated with Y Some experts suggest
breast-feeding mothers use
improved umbilical blood
the lowest effective dose
gases (improvements in
and for the shortest
the umbilical cord
duration taken after
bicarbonate concentration
feeding.
and base deficit)20
apparently by reducing
fetal oxygen demand as
the maternal core
temperature declines.
Y Former suggestion that
first trimester exposure in
combination with
propoxyphene is
associated with clubfoot
and digital abnormalities
is not sustained by large
series tests.21
Y Possible link between
acetaminophen,
gastroschisis, and small
bowel atresia in the
offspring of genetically
predisposed mothers
exposed to the drug early
in pregnancy.22
Y The drug has no
antiplatelet activity and
does not pose a
hemorrhagic risk to the
fetus.23
(continued)
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Table 3. Considerations for Drugs with Minimal or Unknown Teratogenic Effect (continued)
Drug
Ibuprofen (Advil, Alaxan,
Brofen, Motrin,
Paduden)
Antibiotics
Penicillin-G
Tetracycline
(Achromycin,
Telmycin, Tetocyn,
Tetracap)
Maternal Considerations
Fetal Considerations
Breast-Feeding
Considerations
Y Compatible with
Y Drug of choice for management Y Crosses human placenta.
Y Fetal levels are dependent on
breast-feeding.16,17,18
of postabortal pain, acute
Y Some experts suggest
maternal because
postoperative pain, and
breast-feeding mothers use
nonsteroidal
postpartum pain.24,25
the lowest effective dose
antiinflammatory drugs are
and for the shortest
not efficiently metabolized by
duration taken after
the fetal kidney.
feeding.
Y As effective as indomethacin
in closing the ductus
arteriosus but possibly with
less adverse effect on renal
function.26
Y Chronic exposure of the
fetus to the drug requires
close follow-up because of
its potentially lifethreatening effect (fetal
right heart decompensation
after critical constriction of
the ductus arteriosus).
Y Most penicillins cross
Y Penicillin and its derivatives
human placenta.31,32
(ampicillin, cephalosporins) are safe
Y Large clinical experience
and commonly used during
with this drug is
pregnancy.27,28,29,30
reassuring.33
Y Broad-spectrum antibiotic generally
avoided during pregnancy because
of fetal considerations.36
Y Alternative for the treatment of
gonorrhea, syphilis, Listeria
monocytogenes, clostridium species,
Bacillus anthracis, Fusobacterium
fusiforme (Vincent’s infection), and
actinomyces species.
Y When penicillins and
fluoroquinolones are
contraindicated, erythromycin(a
tetracycline-class agent without the
fetal sequelae) is an alternative for
the treatment of gonorrhea and
syphilis37,38; there is consensus that
a test for cure is needed in both
adolescents and pregnant women.39
Y High-risk conditions that require
the treatment of bacterial vaginosis
with oral clindamycin and
erythromycin include women with
prior preterm birth associated with
symptomatic cervicitis, body mass
index less than 19.8, and women
with evidence of endometritis
before pregnancy; a test for cure
should be obtained 1 month later.40
Y Trace amounts enter
human breast milk.34
Y Believed that exposure of the
infant from a mother treated
with this drug is minimal.35
Y Crosses human placenta.
Y Enters human breast milk.
Y May cause a yellow-gray- Y Considered compatible
brown discoloration of the
with breast-feeding.43
41
permanent adult tooth.
Y Unlikely that topically
applied tetracycline
achieves a clinically
relevant systemic level.
Y Oxytetracycline (but not
doxycycline) is associated
with an increased risk of
neural tube defects, cleft
palate, and cardiovascular
defects.
Y Treatment with a
tetracycline derivative, such
as doxycycline, carries little
if any teratogenic risk.42
(continued)
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Table 3. Considerations for Drugs with Minimal or Unknown Teratogenic Effect (continued)
Drug
Maternal Considerations
Fetal Considerations
Breast-Feeding
Considerations
Ciprofloxacin (Ciloxan,
Cipro)
Y Bacteriocidal antibiotic
belonging to the
fluoroquinolone group;
recommended when penicillinclass agents have no effect on
gram-negative rods (eg,
gonorrhea), and it has the best
safety profile of second-line
drugs for drug-resistant
tuberculosis.44
Y Drug of choice for prophylaxis
among asymptomatic pregnant
women exposed to B anthracis
and treatment of Q fever during
pregnancy.45,46
Y Because fluoroquinoloneresistant gonorrhea disease is
being identified more
frequently, fluoroquinolones are
no longer recommended by the
U.S. Centers for Disease Control
and Prevention as first-line therapy
(http://www.cdc.
gov/std/treatment/2006/updatedregimens.htm).
Metronidazole (Flagyl)
Y Used widely during pregnancy Y Crosses human placenta.
Y Excreted into human
to treat bacterial vaginosis,
Y Does not appear to have a
breast milk.
trichomoniasis, inflammatory
teratogenic risk when used Y Considered compatible
bowel disease, C difficile colitis,
at the recommended
with breast-feeding.63
62
and anaerobic and protozoal
doses.
infections.52,53
Y Several large randomized trials
sought to determine whether the
successful treatment of bacterial
vaginosis reduced the
prevalence of adverse outcomes,
such as preterm birth, with
mixed results:54,55,56,57
– treatment of women with
asymptomatic bacterial vaginosis
but no prior preterm birth
apparently does not alter their
risk of preterm delivery.58
– women who deliver preterm
in association with
symptomatic bacterial
vaginosis have a lower risk of
recurrent preterm birth if
treated with clindamycin and
erythromycin but not when
treated with metronidazole.59
Y Concentrated in human
Y Only a small fraction of
breast milk.50
fluoroquinolones
Y Neonatal Clostridium
(ciprofloxacin, ofloxacin,
difficile pseudomembranous
and levofloxacin) cross the
colitis has been reported in
human placenta.47
Y Short-duration treatment
neonates breast-fed by
with ciprofloxacin appears
mothers treated with this
free of adverse fetal
drug.51
responses.
Y The new quinolone,
trovafloxacin, crosses the
placenta but does not
appear to be associated
with an increased risk of
malformation or
musculoskeletal problems
in either animals or
humans.47,48
Y There are no clinically
significant musculoskeletal
dysfunctions reported in
children in utero.48,49
Y Because these studies
included a relatively small
number of children exposed
during the first trimester,
longer follow-up and
magnetic resonance imaging
of the joints may be
warranted to exclude subtle
cartilage and bone damage.
(continued)
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Table 3. Considerations for Drugs with Minimal or Unknown Teratogenic Effect (continued)
Drug
Maternal Considerations
Metronidazole (Flagyl)
(continued)
– metronidazole failed to prevent
preterm birth in women with
asymptomatic trichomoniasis.60
– of major concern is the
observation that, in the great
majority of randomized trials,
the drug was actually associated
with an increased rate of
preterm birth.56,61
Y The absence of benefit coupled
with a potential serious
complication indicates that the
drug should be avoided in
preterm women.
Nitrofurantoin
(Furadantin,
Furantoin,
Macrodantin,
Macrobid)
Y Safe and effective for the
treatment of asymptomatic
bacteriuria as well as acute and
recurrent urinary tract infections:
– resistance rates are less than
10%.
– women with recurrent urinary
tract infections are candidates for
long-term antibiotic prophylaxis.
Y Acute pulmonary reactions to the
drug, presumably immunemediated, are uncommon but
potentially life-threatening.
Y Patients with glucose-6phosphate dehydrogenase
deficiency may experience
hemolytic reactions.
Y Remains unclear how long a
woman with asymptomatic
bacteriuria should be treated;
some suggest that short-term
administration combined with
continued surveillance for
recurrent bacteriuria is sufficient.
Y Pyelonephritis occurs in
approximately 7% of women
despite adequate treatment.
Fetal Considerations
Breast-Feeding
Considerations
Y Unknown whether it
Y Actively transported into
crosses the human
human milk.
placenta.
Y Clinical experience
Y Generally considered
suggests that maternal oral
compatible with pregnancy.
ingestion is not associated
Y No evidence of being a
with neonatal adverse
human teratogen.
event.
Y Although contraindicated
Y Concern remains for
during labor and in
breast-feeding women
newborns, there are no welltreated therapeutically if
documented cases of
they have a family history
hemolytic reactions in
of glucose-6-phosphate
neonates.
dehydrogenase deficiency
or sensitivity to this drug.
Azithromycin (Aruzilina, Y Treatment of choice for
Y Less than 3% of maternally Y Small amounts are
Zithromax)
chlamydia.
administered azithromycin
excreted in breast milk in
crosses the placenta.
a dose-dependent fashion.
Y Used in combination with
artesunate for malaria prophylaxis. Y No adverse effects reported Y No neonatal adverse effects
in humans.
have been reported.
Y Proved an ineffective treatment to
reduce lower genital tract
colonization with Ureaplasma
urealyticum in women with preterm
labor.
Y When combined with
doxycycline, it reduces the risk
of postcesarean
endomyometritis.
(continued)
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Table 3. Considerations for Drugs with Minimal or Unknown Teratogenic Effect (continued)
Drug
Maternal Considerations
Anucholinergics
Whole category
(albuterol, atropine,
dimenhydrinate)
Albuterol (Proventil,
Ventolin)
Fetal Considerations
Breast-Feeding
Considerations
—
—
Y This class of pharmaceutical
compounds reduces the effects
mediated by acetylcholine in the
central and peripheral nervous
systems.
Crosses the human placenta, Y
though the kinetics remain to
be elucidated.
Y
Less than 10% is absorbed
when administered by
inhalation.
No convincing evidence of
teratogenicity after first
trimester exposure.
Y In general, long-term followup studies of infants exposed
to beta-mimetic tocolysis are
reassuring.
Y Previously used for asthma control Y
during pregnancy.64
Y Mean maternal blood pressures
and heart rates were unaffected. Y
Y In some countries, the drug is used as
a tocolytic agent but there is no
evidence that it retards either pretermY
or term labor.
Atropine (Atropen,
Y No adequate reports or wellAtropinol, Atropisol,
controlled studies in pregnant
Borotropin)
women.
Y Generally used for treatment of
symptomatic bradycardia and
organophosphate poisoning and as
an adjunct to anesthesia.
Dimenhydrinate (Amosyt, Y
Biodramina, Dimetabs,
Wehamine)
Y
Unknown whether it enters
human breast milk.
Generally considered
compatible with breast-feeding.
Y Rapidly crosses the human Y Unknown whether it enters
placenta.
human breast milk.
Y Fetus will respond to the
direct administration of this
medication with tachycardia.
Y
Popular agent for the relief of
nausea and vomiting during
Y
pregnancy.
Recent randomized trial concluded
that ginger is as effective as the drug
for the treatment of hyperemesis
gravidarum and has fewer side
effects.65
Y Both dimenhydrinate and
diphenhydramine are considered
treatment options for severe migraine
headache during pregnancy.66
Y Caution is warranted because
several investigators have reported
an increase in uterine activity with
dimenhydrinate.67
Unknown whether it
Y
crosses human placenta.
No indication that this drug
increases the risk of fetal
abnormalities when given Y
at any stage of pregnancy.
Antihypertensives
Whole category
Y Approximately 3% of women take an
(methyldopa,
antihypertensive during pregnancy.68
hydralazine, labetalol, Y ACOG recommends treatment for
women with a systolic blood pressure
propanolol)
higher than 170 mmHg and/or a
diastolic blood pressure above 109
mmHg. 69
—
Excreted in small quantities
into human breast milk, though
the kinetics are yet to be
elucidated.
Long clinical experience is
reassuring.
—
(continued)
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Table 3. Considerations for Drugs with Minimal or Unknown Teratogenic Effect (continued)
Drug
Maternal Considerations
Fetal Considerations
Breast-Feeding
Considerations
Whole category
Y There is no consensus whether
(methyldopa,
lesser degrees of hypertension
hydralazine, labetalol,
require treatment during
propanolol)
pregnancy because
(continued)
antihypertensive therapy improves
only the maternal, not the fetal,
outcome in women with mild to
moderate chronic hypertension.69
Methyldopa (Aldomet,
Alfametildopa)
Y One of the best-studied
antihypertensives during
pregnancy, remaining a popular
agent for the treatment of
moderate to mild
hypertension.70,71
Y Leads to blockage of the
sympathetic nervous system
(centrally and peripherally)
through an alpha-2 receptornegative feedback mechanism.
Y Depending on the patient, the
drug may be suboptimal
because at least 48 to 72 hours
are required to see an effect.
Y Less effective than metoprolol but
as effective as nifedipine, labetalol,
and ketanserin in decreasing both
systolic and diastolic blood
pressure in women with chronic
hypertension.72
Y Most antihypertensive
Y Enters human breast milk.
agents cross the placenta.
Y Breast-fed neonates are
Y Considered safe for use
normotensive.76
during the first trimester of Y Increases the risk of
neonatal hypoglycemia,
pregnancy.73
Y Neither significantly alters
but this effect may be
fetal cardiac activity nor
blunted by supplementing
produces fetal
with glucose-fortified
hemodynamic changes as
formula.77
measured by Doppler
velocimetry.74
Y Recently, the effects of
various antihypertensive
medications on
fetoplacental circulation
were studied in vitro:75
– in contrast to labetalol,
hydralazine, nifedipine,
and magnesium sulfate,
methyldopa was less
likely to produce
significant direct effects
on fetal vasculature.
Y Other studies suggest the
drug decreases placental
vascular resistance in mild
preeclampsia and in
chronic hypertension.
Hydralazine (Apresoline) Y Hydralazine and labetalol are
Y Most antihypertensive
the most widely used drugs for
agents cross the placenta.
the treatment of acute
Y Clinical experience
hypertension during
suggests the drug is safe
pregnancy.78
during the first trimester.
Y Mechanism of action is
incompletely understood, but it
has been proposed that
hydralazine works through a
cyclic guanosine
monophosphate–mediated
mechanism, resulting in smooth
muscle relaxation.
Y In two recent randomized trials,
the drug was as safe and as
effective as diazoxide and
labetalol for the treatment of
hypertensive emergencies
during the antenatal and
postpartal periods.79,80
Y Enters human breast milk.
Y Breast-fed neonates are
normotensive.76
(continued)
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Table 3. Considerations for Drugs with Minimal or Unknown Teratogenic Effect (continued)
Drug
Maternal Considerations
Breast-Feeding
Considerations
Fetal Considerations
Labetalol (Coreton,
Normo-dyne,
Trandate)
Y Hydralazine and labetalol are
the most widely used drugs for
the treatment of acute
hypertension during
pregnancy.78
Y Combines alpha- and betaadrenoceptor antagonist
properties.
Y When given intravenously, the
drug is associated with a higher
risk of hypotension and cesarean
delivery than diazoxide.81
Propanalol (Inderal)
Y Used extensively during
Y Most antihypertensive
pregnancy for the treatment of
agents cross the placenta.
maternal hypertension,
arrhythmia, and migraine
headache.66
Y Generally considered safe unless
the dose given compromises
maternal cardiac output.
Y Also used acutely to provide
relief of symptoms from
thyrotoxicosis and
pheochromocytoma.86,87
Y Studies of use for hypertension
are small; it appears as effective
as methyldopa and is often
coupled with other hypotensive
agents such as hydralazine.88
Y Enters human breast milk.
Y Breast-fed neonates are
normotensive.76
Y Unknown whether it
Y Not adequately studied in
crosses the human
human pregnancy.
placenta.
Y Commonly prescribed for
Y Not known as a human
allergic rhinitis during
teratogen.
pregnancy.
Y The advantage of this drug over
many other antihistaminic drugs
is that it does not cause
clinically significant cardiac QTinterval prolongation.89
Y Enters human breast milk.
Y Irritability is the most
common adverse reaction
reported in the newborns
of women using
antihistamines while
breast-feeding. .
Antihistamines
Cetirizine (Zyrtec)
Y Enters human breast milk.
Y Most antihypertensive
Y Breast-fed neonates are
agents cross the placenta.
normotensive.7
Y Large doses given
intravenously can cause fetal
bradycardia, hypoglycemia,
hypotension, pericardial
effusion, myocardial
hypertrophy, and fetal death
due to acute hypotension:82,83
– based on these risks, an
initial intravenous dose of
5–10 mg is recommended
– similar responses are
unlikely with oral therapy.
Y Overall, neonatal outcome is
similar to that achieved with
hydralazine.84
Y May be useful for the
treatment of fetal
thyrotoxicosis.85
(continued)
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OBSTETRICS & GYNECOLOGY
Table 3. Considerations for Drugs with Minimal or Unknown Teratogenic Effect (continued)
Drug
Maternal Considerations
Cetirizine (Zyrtec)
(continued)
Y The product label may state that
medications for allergic rhinitis
should be avoided during
pregnancy because of a lack of
fetal safety, but the majority of
human data refutes this position.
Diphenhy-dramine
(Benadryl)
Y Not adequately studied in
human pregnancy.
Y Useful adjunct for women who
have allergic reactions to local
anesthesia, laminaria, and serum
albumin and for the treatment of
severe migraine headaches.90,91
Antivirals
Acyclovir
Corticosteroids
Whole category
(prednisone,
betamethasone,
dexamethasone)
Fetal Considerations
Breast-Feeding
Considerations
Y Crosses the human placenta Y Unknown whether it enters
but, the kinetics remain to
breast milk.
be elucidated.
Y Irritability is the most
Y No evidence of increased
common adverse reaction
fetal risk if administered
reported in the newborns of
during any stage of
women using antihistamines
pregnancy.
while breast-feeding
Y May cause neonatal
depression if administered
during labor.
Y
Y All suspected herpes virus
Y
infections should be confirmed
through viral or serological
testing.92
Y Treatment of genital herpes with
this drug during pregnancy is not Y
curative but does reduce the
duration of symptoms and viral
shedding.93
Y Long clinical experience is
reassuring.
Y Based on several studies, ACOG
recommends prophylactic acyclovir
at 36 weeks to reduce the risks of
recurrent genital herpes and thus
potentially avoid cesarean
delivery.94
Y Suppression therapy is both
effective and cost-effective whether
or not the primary infection occurs
during the current pregnancy.
Crosses the human placenta. Y
Concentrated in the amniotic
fluid, but there is no evidence
Y
of preferential drug
accumulation in the fetus.95
Long-term follow-up studies
have not revealed any increase
in or pattern of malformations
after exposure during the first
trimester.96
Y Corticosteroids may increase the Y
risk of maternal infection in
women with preterm premature
rupture of the fetal membranes,
though most large studies reveal Y
no such increased risk.98
Y Can transiently cause an abnormal
glucose tolerance test, 99 worsen
existing diabetes mellitus, and are Y
associated with pulmonary edema
when given with a tocolytic agent
Y
in the setting of an underlying
infection.100
Y Repeat doses of corticosteroids do
not reduce the maternal perception
of fetal movements.101
The evidence that
corticosteroids are human
teratogens is weak and
confined to cleft lip.102,103,104,105
An increased risk of neonatal
sepsis is suggested but not
confirmed despite large
prospective studies.
Multiple courses of
corticosteroids are not
recommended.106
Adverse effects noted in
animal and human studies
include a profound
suppression of fetal breathing,
movement, impaired
Secreted and achieves
concentrations in breast milk
higher than maternal serum.97
Considered compatible with
breast-feeding.
(continued)
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427
Table 3. Considerations for Drugs with Minimal or Unknown Teratogenic Effect (continued)
Drug
Maternal Considerations
Corticosteroids
Whole category
(prednisone,
betamethasone,
dexamethasone)
(continued)
Breast-Feeding
Considerations
Fetal Considerations
Y
myelination, intrauterine
growth restriction, and
microcephaly.107,108
Y There is controversy as to the
earliest gestational age at which
corticosteroids can be
administered to improve fetal
outcome:109
– the Eunice Kennedy Shriver
National Institute of Child
Health and Human
Development and the Office
of Medical Applications of
Research of the National
Institutes of Health
recommend a single course of
corticosteroids to all pregnant
women between 24 and 34
weeks of gestation who are at
risk of preterm delivery
within 7 days.110
Y Repeat corticosteroid courses,
including so-called “rescue
therapy,” should not be used
routinely.
Y Recently, it was demonstrated
that repeat doses of
corticosteroids are
accompanied by a reduction in
birth weight and an increase in
the prevalence of small for
gestational age infants.111
There are no adequate
reports or well-controlled
studies in breast-feeding
women.
Prednisone (Cortan,
Dacortin)
Y No adequate well-controlled
Y Human placenta metabolizes Y Unknown whether enters
studies during pregnancy.
prednisone reducing fetal
human breast milk.
Y Several trials show that women
exposure to less than 10% of Y Long clinical experience
with antiphospholipid syndrome
the maternal level.113
suggests this drug is
treated with prednisone and
compatible with breastaspirin have higher loss rates
feeding.
than women treated with
heparin and aspirin.112
Betamethasone
(Celestone)
Y Crosses the human placenta Y Still unclear whether
Y Routinely used for the
and is proven to enhance
maternal treatment with
acceleration of fetal lung
perinatal outcome after
this drug increases the
maturity; administration is
preterm birth.116
concentration of cortisone
standard of care for threatened
Y Some studies suggest this
in breast milk.
preterm birth.114,115
drug can alter fetal breathing
when administered for the
enhancement of lung
maturation.117
(continued)
428
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OBSTETRICS & GYNECOLOGY
Table 3. Considerations for Drugs with Minimal or Unknown Teratogenic Effect (continued)
Breast-Feeding
Considerations
Drug
Dexamethasone
(Decadron)
Maternal Considerations
Fetal Considerations
Y Routinely used for the
Y Crosses the human placenta Y Still unclear whether
acceleration of fetal lung
and is proven to enhance
maternal treatment with
maturity; administration is
perinatal outcome after
this drug increases the
standard of care for threatened
preterm birth.116
concentration of cortisone
Y Complete fetal heart block has
preterm birth.114,115
in breast milk.
Y Effective antiemetic after
been treated successfully with
general anesthesia for
this drug:121
– after corticosteroid
pregnancy termination.118
administration, the fetal heart
rate pattern may become
transiently nonreactive.122
Y Can prevent or diminish
virilization due to congenital
adrenal hyperplasia if
administered early during the
first trimester.123,124
Y Some reports show that the drug
intravenously modifies the clinical
course of the hemolytic anemia,
elevated liver enzymes, and lowplatelet count syndrome during
both the antenatal and postpartal
periods119; however, a more recent
study contradicts that
conclusion.120
ACOG, American College of Obstetricians and Gynecologists.
nized drugs currently classified as safe for pregnant and
breast-feeding women. As demonstrated, that classification is not always warranted or is applied before adequate evidence proves it so. As discussed in Part I, novel
approaches in the field of theranostics are being developed to address this research shortfall. Meanwhile,
physicians should look more critically at a drug’s classification and evidence of its teratogenicity before prescribing it. Clinicians should become familiar with all of
the aspects of the drugs they prescribe, in addition to the
controversies surrounding them, through consultation
with maternal–fetal medicine specialists and through
references and Web sites providing up-to-date information in an effort to promote safer prescribing practices.
REFERENCES
1. Li DK, Liu L, Odouli R. Exposure to non-steroidal antiinflammatory drugs during pregnancy and risk of miscarriage: population based cohort study. BMJ 2003;327:368.
2. Buhimschi CS, Weiner CP. Medications in pregnancy and
lactation. In: Queenan JT, Spong CY, Lockwood CJ, editors.
Management of high-risk pregnancy: an evidence-based
approach. 5th ed. Malden (MA): Blackwell Publishing Ltd;
2007. p. 38–58.
3. Rainsford KD. Anti-inflammatory drugs in the 21st century.
Subcell Biochem 2007;42:3–27.
VOL. 113, NO. 2, PART 1, FEBRUARY 2009
4. Everson GW, Krenzelok EP. Chronic salicylism in a patient
with juvenile rheumatoid arthritis. Clin Pharm 1986;5:
334–41.
5. Kozer E, Costei AM, Boskovic R, Nulman I, Nikfar S, Koren
G. Effects of aspirin consumption during pregnancy on
pregnancy outcomes: meta-analysis. Birth Defects Res B Dev
Reprod Toxicol 2003;68:70–84.
6. James AH, Brancazio LR, Price T. Aspirin and reproductive
outcomes. Obstet Gynecol Surv 2008;63:49–57.
7. Nadar S, Blann AD, Lip GY. Effects of aspirin on intraplatelet vascular endothelial growth factor, angiopoietin-1,
and p-selectin levels in hypertensive patients. Am J Hypertens
2006;19:970–7.
8. Empson M, Lassere M, Craig JC, Scott JR. Recurrent pregnancy loss with antiphospholipid antibody: a systematic
review of therapeutic trials. Obstet Gynecol 2002;99:135–44.
9. Di Nisio M, Peters L, Middeldorp S. Anticoagulants for the
treatment of recurrent pregnancy loss in women without
antiphospholipid syndrome. The Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD004734. DOI:
10.1002/14651858.CD004734.
10. Farquharson RG, Quenby S, Greaves M. Antiphospholipid
syndrome in pregnancy: a randomized, controlled trial of
treatment [published erratum appears in Obstet Gynecol
2002;100:1361]. Obstet Gynecol 2002;100:408–13.
11. Caritis S, Sibai B, Hauth J, Lindheimer MD, Klebanoff M,
Thom E, et al. Low-dose aspirin to prevent preeclampsia in
women at high risk. National Institute of Child Health and
Human Development Network of Maternal-Fetal Medicine
Units. N Engl J Med 1998;338:701–5.
Buhimschi and Weiner
Medications in Pregnancy and Lactation
429
12. Vainio M, Kujansuu E, Iso-Mustajarvi M, Maenpaa J. Low
dose acetylsalicylic acid in prevention of pregnancy-induced
hypertension and intrauterine growth retardation in women
with bilateral uterine artery notches. BJOG 2002;109:161–7.
13. Askie LM, Duley L, Henderson-Smart DJ, Stewart LA,
PARIS Collaborative Group. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient
data. Lancet 2007;369:1791–8.
14. Martinez-Frias ML, Rodriguez-Pinilla E, Prieto L. Prenatal
exposure to salicylates and gastroschisis: a case-control study.
Teratology 1997;56:241–3.
15. Kozer E, Nikfar S, Costei A, Boskovic R, Nulman I, Koren G.
Aspirin consumption during the first trimester of pregnancy
and congenital anomalies: a meta-analysis. Am J Obstet
Gynecol 2002;187:1623–30.
31. Pacifici GM. Placental transfer of antibiotics administered to
the mother: a review. Int J Clin Pharmacol Ther 2006;44:
57–63.
32. Elek E, Ivan E, Arr M. Passage of penicillins from mother to
foetus in humans. Int J Clin Pharmacol 1972;6:223–8.
33. Dashe JS, Gilstrap LC 3rd. Antibiotic use in pregnancy.
Obstet Gynecol Clin North Am 1997;24:617–29.
34. Nau H. Clinical pharmacokinetics in pregnancy and perinatology. II. Penicillins. Dev Pharmacol Ther 1987;10:174–98.
35. Matheson I, Samseth M, Sande HA. Ampicillin in breast milk
during puerperal infections. Eur J Clin Pharmacol 1988;34:
657–9.
36. Stauffer UG. Tooth changes caused by tetracycline in the
fetus, infant and child [in German]. Schweiz Med Wochenschr 1967;97:291–3.
16. Bar-Oz B, Bulkowstein M, Benyamini L, Greenberg R, Soriano I, Zimmerman D, et al. Use of antibiotic and analgesic
drugs during lactation. Drug Saf 2003;26:925–35.
37. ElTabbakh GH, Elejalde BR, Broekhuizen FF. Primary syphilis and nonimmune fetal hydrops in a penicillin-allergic
woman. A case report. J Reprod Med 1994;39:412–4.
17. Bleyer WA, Breckenridge RT. Studies on the detection of
adverse drug reactions in the newborn. II. The effects of
prenatal aspirin on newborn hemostasis. JAMA 1970;213:
2049–53.
38. Smith JR, Taylor-Robinson D. Infection due to Chlamydia
trachomatis in pregnancy and the newborn. Baillieres Clin
Obstet Gynaecol 1993;7:237–55.
18. Spigset O, Hagg S. Analgesics and breast-feeding: safety
considerations. Paediatr Drugs 2000;2:223–38.
19. Acetylcysteine (Acetadote) for acetaminophen overdosage.
Med Lett Drugs Ther 2005;47:70–1.
20. Kirshon B, Moise KJ Jr, Wasserstrum N. Effect of acetaminophen on fetal acid-base balance in chorioamnionitis. J
Reprod Med 1989;34:955–9.
21. Golden NL, King KC, Sokol RJ. Propoxyphene and acetaminophen. Possible effects on the fetus. Clin Pediatr (Phila)
1982;21:752–4.
22. Adjei AA, Gaedigk A, Simon SD, Weinshilboum RM, Leeder
JS. Interindividual variability in acetaminophen sulfation by
human fetal liver: implications for pharmacogenetic investigations of drug-induced birth defects. Birth Defects Res A
Clin Mol Teratol 2008;82:155–65.
23. Collins E. Maternal and fetal effects of acetaminophen and
salicylates in pregnancy. Obstet Gynecol 1981;58 suppl:
57S–62S.
24. Sunshine A, Olson NZ, O’Neill E, Ramos I, Doyle R.
Analgesic efficacy of a hydrocodone with ibuprofen combination compared with ibuprofen alone for the treatment of
acute postoperative pain. J Clin Pharmacol 1997;37:908–15.
25. Wiebe ER, Rawling M. Pain control in abortion. Int J
Gynaecol Obstet 1995;50:41–6.
26. Thomas RL, Parker GC, Van Overmeire B, Aranda JV. A
meta-analysis of ibuprofen versus indomethacin for closure of
patent ductus arteriosus. Eur J Pediatr 2005;164:135–40.
27. Watson-Jones D, Gumodoka B, Weiss H, Changalucha J,
Todd J, Mugeye K, et al. Syphilis in pregnancy in Tanzania.
II. The effectiveness of antenatal syphilis screening and
single-dose benzathine penicillin treatment for the prevention
of adverse pregnancy outcomes. J Infect Dis 2002;186:
948–57.
28. Michelow IC, Wendel GD Jr, Norgard MV, Zeray F, Leos
NK, Alsaadi R, et al. Central nervous system infection in
congenital syphilis. N Engl J Med 2002;346:1792–8.
29. Ballard RC, Berman SM, Fenton KA. Azithromycin versus
penicillin for early syphilis. N Engl J Med 2006;354:203–5.
30. Boyer KM, Gotoff SP. Prevention of early-onset neonatal
group B streptococcal disease with selective intrapartum
chemoprophylaxis. N Engl J Med 1986;314:1665–9.
430
Buhimschi and Weiner
39. Sexually transmitted diseases in adolescents. ACOG Committee Opinion No. 301. American College of Obstetricians
and Gynecologists Committee on Adolescent Health Care.
Obstet Gynecol 2004;104:891–8.
40. McGregor JA, French JI. Bacterial vaginosis in pregnancy.
Obstet Gynecol Surv 2000;55 suppl:S1–19.
41. Klastersky-Genot MT. Effects of tetracycline, administered
during pregnancy, on the deciduous teeth. A double blind
controlled study [in French]. Acta Stomatol Belg 1970;67:
107–24.
42. Czeizel AE, Rockenbauer M. Teratogenic study of doxycycline. Obstet Gynecol 1997;89:524–8.
43. Hendeles L, Trask PA. Tetracycline and lactation. J Am Dent
Assoc 1983;107:12, 14.
44. Bothamley G. Drug treatment for tuberculosis during pregnancy: safety considerations. Drug Saf 2001;24:553–65.
45. Centers for Disease Control and Prevention (CDC). Updated
recommendations for antimicrobial prophylaxis among
asymptomatic pregnant women after exposure to Bacillus
anthracis. MMWR Morb Mortal Wkly Rep 2001;50:960.
46. Ludlam H, Wreghitt TG, Thornton S, Thomson BJ, Bishop
NJ, Coomber S, et al. Q fever in pregnancy. J Infect 1997;
34:75–8.
47. Polachek H, Holcberg G, Sapir G, Tsadkin-Tamir M, Polachek J, Katz M, et al. Transfer of ciprofloxacin, ofloxacin and
levofloxacin across the perfused human placenta in vitro. Eur
J Obstet Gynecol Reprod Biol 2005;122:61–5.
48. Casey B, Bawdon RE. Ex vivo human placental transfer of
trovafloxacin. Infect Dis Obstet Gynecol 2000;8:228–9.
49. Peled Y, Friedman S, Hod M, Merlob P. Ofloxacin during the
second trimester of pregnancy. DICP 1991;25:1181–2.
50. Giamarellou H, Kolokythas E, Petrikkos G, Gazis J, Aravantinos D, Sfikakis P. Pharmacokinetics of three newer quinolones in pregnant and lactating women. Am J Med 1989;87:
49S–51S.
51. Harmon T, Burkhart G, Applebaum H. Perforated
pseudomembranous colitis in the breast-fed infant. J Pediatr
Surg 1992;27:744–6.
52. Connell W, Miller A. Treating inflammatory bowel disease
during pregnancy: risks and safety of drug therapy [published
erratum appears in Drug Saf 1999;21:456]. Drug Saf 1999;21:
311–23.
Medications in Pregnancy and Lactation
OBSTETRICS & GYNECOLOGY
53. Gulmezoglu AM. Interventions for trichomoniasis in pregnancy.
The Cochrane Database of Systematic Reviews 2002, Issue 3. Art.
No.: CD000220. DOI: 10.1002/14651858.CD000220.
72. Livingstone I, Craswell PW, Bevan EB, Smith MT, Eadie MJ.
Propranolol in pregnancy three year prospective study. Clin
Exp Hypertens B 1983;2:341–50.
54. Klebanoff MA, Hauth JC, MacPherson CA, Carey JC, Heine
RP, Wapner RJ, et al. Time course of the regression of
asymptomatic bacterial vaginosis in pregnancy with and
without treatment. Am J Obstet Gynecol 2004;190:363–70.
73. Elhassan EM, Mirghani OA, Habour AB, Adam I. Methyldopa versus no drug treatment in the management of mild
pre-eclampsia. East Afr Med J 2002;79:172–5.
55. Klebanoff MA, Hillier SL, Nugent RP, MacPherson CA,
Hauth JC, Carey JC et al. Is bacterial vaginosis a stronger risk
factor for preterm birth when it is diagnosed earlier in
gestation? Am J Obstet Gynecol 2005;192:470–7.
56. Okun N, Gronau KA, Hannah ME. Antibiotics for bacterial
vaginosis or Trichomonas vaginalis in pregnancy: a systematic review. Obstet Gynecol 2005;105:857–68.
57. Hauth JC, Goldenberg RL, Andrews WW, DuBard MB,
Copper RL. Reduced incidence of preterm delivery with
metronidazole and erythromycin in women with bacterial
vaginosis. N Engl J Med 1995;333:1732–6.
58. Carey JC, Klebanoff MA, Hauth JC, Hillier SL, Thom EA,
Ernest JM, et al. Metronidazole to prevent preterm delivery in
pregnant women with asymptomatic bacterial vaginosis.
National Institute of Child Health and Human Development
Network of Maternal-Fetal Medicine Units. N Engl J Med
2000;342:534–40.
59. Goldenberg RL, Klebanoff M, Carey JC, Macpherson C.
Metronidazole treatment of women with a positive fetal
fibronectin test result. Am J Obstet Gynecol 2001;185:485–6.
60. Klebanoff MA, Carey JC, Hauth JC, Hillier SL, Nugent RP,
Thom EA, et al. Failure of metronidazole to prevent preterm
delivery among pregnant women with asymptomatic Trichomonas vaginalis infection. N Engl J Med 2001;345:487–93.
61. Shennan A, Crawshaw S, Briley A, Hawken J, Seed P, Jones
G, et al. A randomised controlled trial of metronidazole for
the prevention of preterm birth in women positive for cervicovaginal fetal fibronectin: the PREMET Study. BJOG 2006;
113:65–74.
74. Gunenc O, Cicek N, Gorkemli H, Celik C, Acar A, Akyurek
C. The effect of methyldopa treatment on uterine, umbilical
and fetal middle cerebral artery blood flows in preeclamptic
patients. Arch Gynecol Obstet 2002;266:141–4.
75. Houlihan DD, Dennedy MC, Ravikumar N, Morrison JJ.
Anti-hypertensive therapy and the feto-placental circulation:
effects on umbilical artery resistance. J Perinat Med 2004;32:
315–9.
76. Beardmore KS, Morris JM, Gallery ED. Excretion of antihypertensive medication into human breast milk: a systematic
review. Hypertens Pregnancy 2002;21:85–95.
77. Munshi UK, Deorari AK, Paul VK, Singh M. Effects of
maternal labetalol on the newborn infant. Indian Pediatr
1992;29:1507–12.
78. Scardo JA, Vermillion ST, Newman RB, Chauhan SP, Hogg
BB. A randomized, double-blind, hemodynamic evaluation of
nifedipine and labetalol in preeclamptic hypertensive emergencies. Am J Obstet Gynecol 1999;181:862–6.
79. Hennessy A, Thornton CE, Makris A, Ogle RF, HendersonSmart DJ, Gillin AG, et al. A randomised comparison of
hydralazine and mini-bolus diazoxide for hypertensive emergencies in pregnancy: the PIVOT trial. Aust N Z J Obstet
Gynaecol 2007;47:279–85.
80. Vigil-De Gracia P, Ruiz E, López JC, de Jaramillo IA,
Vega-Maleck JC, Pinzón J. Management of severe hypertension in the postpartum period with intravenous hydralazine or
labetalol: a randomized clinical trial. Hypertens Pregnancy
2007;26:163–71.
62. Heisterberg L. Placental transfer of metronidazole in the first
trimester of pregnancy. J Perinat Med 1984;12:43–5.
81. Duley L, Henderson-Smart DJ, Meher S. Drugs for treatment
of very high blood pressure during pregnancy. The Cochrane
Database of Systematic Reviews 2006, Issue 3. Art. No.:
CD001449. DOI: 10.1002/14651858.CD001449.
63. Passmore CM, McElnay JC, Rainey EA, D’Arcy PF. Metronidazole excretion in human milk and its effect on the
suckling neonate. Br J Clin Pharmacol 1988;26:45–51.
82. Olsen KS, Beier-Holgersen R. Fetal death following labetalol
administration in pre-eclampsia. Acta Obstet Gynecol Scand
1992;71:145–7.
64. Wendel PJ, Ramin SM, Barnett-Hamm C, Rowe TF, Cunningham FG. Asthma treatment in pregnancy: a randomized
controlled study. Am J Obstet Gynecol 1996;175:150–4.
83. Crooks BN, Deshpande SA, Hall C, Platt MP, Milligan DW.
Adverse neonatal effects of maternal labetalol treatment.
Arch Dis Child Fetal Neonatal Ed 1998;79:F150–1.
65. Pongrojpaw D, Somprasit C, Chanthasenanont A. A randomized comparison of ginger and dimenhydrinate in the treatment of nausea and vomiting in pregnancy. J Med Assoc Thai
2007;90:1703–9.
84. Hjertberg R, Faxelius G, Belfrage P. Comparison of outcome
of labetalol or hydralazine therapy during hypertension in
pregnancy in very low birth weight infants. Acta Obstet
Gynecol Scand 1993;72:611–5.
66. Aubé M. Migraine in pregnancy. Neurology 1999;53:S26–8.
85. Bowman ML, Bergmann M, Smith JF. Intrapartum labetalol
for the treatment of maternal and fetal thyrotoxicosis. Thyroid 1998;8:795–6.
67. Hay TB, Wood C. The effect of dimenhydrinate on uterine
contractions. Aust N Z J Obstet Gynaecol 1967;7:81–9.
68. Andrade SE, Raebel MA, Brown J, Lane K, Livingston J,
Boudreau D, et al. Outpatient use of cardiovascular drugs
during pregnancy. Pharmacoepidemiol Drug Saf 2008;17:
240–7.
69. Chronic hypertension in pregnancy. ACOG Practice Bulletin.
American College of Obstetricians and Gynecologists. Obstet
Gynecol 2001;98 suppl: 177–85.
70. Borghi C, Esposti DD, Cassani A, Immordino V, Bovicelli L,
Ambrosioni E. The treatment of hypertension in pregnancy.
J Hypertens Suppl 2002;20:S52–6.
71. Kirsten R, Nelson K, Kirsten D, Heintz B. Clinical pharmacokinetics of vasodilators. Part II. Clin Pharmacokinet 1998;
35:9–36.
VOL. 113, NO. 2, PART 1, FEBRUARY 2009
86. Caswell HT, Marks AD, Channick BJ. Propranolol for the
preoperative preparation of patients with thyrotoxicosis. Surg
Gynecol Obstet 1978;146:908–10.
87. Sukenik S, Biale Y, Ben-Aderet N, Khodadadi J, Levi D, Stern
J. Successful control of pheochromocytoma in pregnancy.
Case report. Eur J Obstet Gynecol Reprod Biol 1979;9:
249–51.
88. Bott-Kanner G, Schweitzer A, Reisner SH, Joel-Cohen SJ,
Rosenfeld JB. Propranolol and hydralazine in the management of essential hypertension in pregnancy. Br J Obstet
Gynecol 1980;87:110–4.
89. Reichmuth D, Lockey RF. Present and potential therapy for
allergic rhinitis: a review. BioDrugs 2000;14:371–87.
Buhimschi and Weiner
Medications in Pregnancy and Lactation
431
90. Chanda M, Mackenzie P, Day JH. Hypersensitivity reactions
following laminaria placement. Contraception 2000;62:
105–6.
91. Stafford CT, Lobel SA, Fruge BC, Moffitt JE, Hoff RG, Fadel
HE. Anaphylaxis to human serum albumin. Ann Allergy
1988;61:85–8.
92. Management of herpes in pregnancy. ACOG Practice Bulletin No. 82. American College of Obstetricians and Gynecologists. Obstet Gynecol 2007;109:1489–98.
93. Scott LL, Hollier LM, McIntire D, Sanchez PJ, Jackson GL,
Wendel GD Jr. Acyclovir suppression to prevent recurrent
genital herpes at delivery. Infect Dis Obstet Gynecol 2002;
10:71–7.
94. Little SE, Caughey AB. Acyclovir prophylaxis for pregnant
women with a known history of herpes simplex virus: a
cost-effectiveness analysis. Am J Obstet Gynecol 2005;193:
1274–9.
95. Kimberlin DF, Weller S, Whitley RJ, Andrews WW, Hauth
JC, Lakeman F, et al. Pharmacokinetics of oral valacyclovir
and acyclovir in late pregnancy. Am J Obstet Gynecol
1998;179:846–51.
96. Laerum OD. Toxicology of acyclovir. Scand J Infect Dis
Suppl 1985;47:40–3.
97. Sheffield JS, Fish DN, Hollier LM, Cadematori S, Nobles BJ,
Wendel GD Jr. Acyclovir concentrations in human breast
milk after valacyclovir administration. Am J Obstet Gynecol
2002;186:100–2.
98. Egerman RS, Mercer BM, Doss JL, Sibai BM. A randomized,
controlled trial of oral and intramuscular dexamethasone in
the prevention of neonatal respiratory distress syndrome.
Am J Obstet Gynecol 1998;179:1120–3.
99. Gurbuz A, Karateke A, Ozturk G, Kabaca C. Is 1-hour
glucose screening test reliable after a short-term administration of antenatal betamethasone? Am J Perinatol 2004;21:
415–20.
100. Elliott JP, O’Keeffe DF, Greenberg P, Freeman RK. Pulmonary edema associated with magnesium sulfate and betamethasone administration. Am J Obstet Gynecol 1979;134:
717–9.
101. Mushkat Y, Ascher-Landsberg J, Keidar R, Carmon E,
Pauzner D, David MP. The effect of betamethasone versus
dexamethasone on fetal biophysical parameters. Eur J Obstet
Gynecol Reprod Biol 2001;97:50–2.
102. Lockshin MD, Sammaritano LR. Corticosteroids during pregnancy. Scand J Rheumatol Suppl 1998;107:136–8.
103. Walker BE. Induction of cleft palate in rats with antiinflammatory drugs. Teratology 1971;4:39–42.
104. Park-Wyllie L, Mazzotta P, Pastuszak A, Moretti ME, Beique
L, Hunnisett L, et al. Birth defects after maternal exposure to
corticosteroids: prospective cohort study and meta-analysis of
epidemiological studies. Teratology 2000;62:385–92.
105. Carmichael SL, Shaw GM, Ma C, Werler MM, Rasmussen
SA, Lammer EJ. National Birth Defects Prevention Study.
Maternal corticosteroid use and orofacial clefts. Am J Obstet
Gynecol 2007;197:585.e1–7.
106. Spinillo A, Viazzo F, Colleoni R, Chiara A, Maria Cerbo R,
Fazzi E. Two-year infant neurodevelopmental outcome after
single or multiple antenatal courses of corticosteroids to
prevent complications of prematurity. Am J Obstet Gynecol
2004;191:217–24.
107. Huang WL, Harper CG, Evans SF, Newnham JP, Dunlop SA.
Repeated prenatal corticosteroid administration delays myeli-
432
Buhimschi and Weiner
nation of the corpus callosum in fetal sheep. Int J Dev
Neurosci 2001;19:415–25.
108. Whitelaw A, Thoresen M. Antenatal steroids and the developing brain. Arch Dis Child Fetal Neonatal Ed 2000;83:
F154–7.
109. Hayes EJ, Paul DA, Stahl GE, Seibel-Seamon J, Dysart K,
Leiby BE, et al. Effect of antenatal corticosteroids on survival
for neonates born at 23 weeks of gestation. Obstet Gynecol
2008;111:921–6.
110. Antenatal corticosteroid therapy for fetal maturation. ACOG
Committee Opinion. American College of Obstetricians and
Gynecologists Committee on Obstetric Practice. Obstet
Gynecol 2002;99:871–3.
111. Wapner RJ, Sorokin Y, Thom EA, Johnson F, Dudley DJ,
Spong CY, et al. Single versus weekly courses of antenatal
corticosteroids: evaluation of safety and efficacy. Am J Obstet
Gynecol 2006;195:633–42.
112. Silver RK, MacGregor SN, Sholl JS, Hobart JM, Neerhof
MG, Ragin A. Comparative trial of prednisone plus aspirin
versus aspirin alone in the treatment of anticardiolipin antibody-positive obstetric patients. Am J Obstet Gynecol 1993;
169:1411–7.
113. Addison RS, Maguire DJ, Mortimer RH, Cannell GR. Metabolism of prednisolone by the isolated perfused human placental lobule. J Steroid Biochem Mol Biol 1991;39:83–90.
114. Lieman JM, Brumfield CG, Carlo W, Ramsey PS. Preterm
premature rupture of membranes: is there an optimal gestational age for delivery? Obstet Gynecol 2005;105:12–7.
115. Walfisch A, Hallak M, Mazor M. Multiple courses of antenatal
steroids: risks and benefits. Obstet Gynecol 2001;98:491–7.
116. Effect of corticosteroids for fetal maturation on perinatal
outcomes. NIH Consens Statement 1994;12:1–24.
117. Mulder EJ, Derks JB, Visser GH. Antenatal corticosteroid
therapy and fetal behaviour: a randomised study of the effects
of betamethasone and dexamethasone. Br J Obstet Gynaecol
1997;104:1239–47.
118. Fujii Y, Uemura A. Dexamethasone for the prevention of
nausea and vomiting after dilatation and curettage: a randomized controlled trial. Obstet Gynecol 2002;99:58–62.
119. Martin JN Jr, Thigpen BD, Rose CH, Cushman J, Moore A,
May WL. Maternal benefit of high-dose intravenous corticosteroid therapy for HELLP syndrome. Am J Obstet Gynecol
2003;189:830–4.
120. Fonseca JE, Mendez F, Catano C, Arias F. Dexamethasone
treatment does not improve the outcome of women with
HELLP syndrome: a double-blind, placebo-controlled, randomized clinical trial. Am J Obstet Gynecol 2005;193:
1591–8.
121. Costedoat-Chalumeau N, Georgin-Lavialle S, Amoura Z,
Piette JC. Anti-SSA/Ro and anti-SSB/La antibody-mediated
congenital heart block. Lupus 2005;14:660–4.
122. Rotmensch S, Lev S, Kovo M, Efrat Z, Zahavi Z, Lev N, et al.
Effect of betamethasone administration on fetal heart rate
tracing: a blinded longitudinal study. Fetal Diagn Ther 2005;
20:371–6.
123. Hughes I. Prenatal treatment of congenital adrenal hyperplasia:
do we have enough evidence? Treat Endocrinol 2006;5:1–6.
124. Brook CG. Antenatal treatment of a mother bearing a fetus
with congenital adrenal hyperplasia. Arch Dis Child Fetal
Neonatal Ed 2000;82:F176–81.
Medications in Pregnancy and Lactation
OBSTETRICS & GYNECOLOGY