A Review of Antibiotic Use in Pregnancy

P. Brandon Bookstaver,1,* Christopher M. Bland,2 Brooke Griffin,3 Kayla R. Stover,4 Lea S. Eiland,5
and Milena McLaughlin,3
1

Department of Clinical Pharmacy and Outcomes Sciences, South Carolina College of Pharmacy, University of
South Carolina, Columbia, South Carolina; 2Department of Clinical and Administrative Pharmacy, University of
Georgia College of Pharmacy, Savannah, Georgia; 3Department of Pharmacy Practice, Midwestern University
Chicago College of Pharmacy, Downers Grove, Illinois; 4Department of Pharmacy Practice, University of
Mississippi School of Pharmacy, Jackson, Mississippi; 5Department of Pharmacy Practice, Auburn University
Harrison School of Pharmacy, Meridian, Mississippi

During pregnancy, untreated sexually transmitted or urinary tract infections are associated with significant morbidity, including low birth weight, preterm birth, and spontaneous abortion. Approximately
one in four women will be prescribed an antibiotic during pregnancy, accounting for nearly 80% of
prescription medications in pregnant women. Antibiotic exposures during pregnancy have been associated with both short-term (e.g., congenital abnormalities) and long-term effects (e.g., changes in gut
microbiome, asthma, atopic dermatitis) in the newborn. However, it is estimated that only 10% of
medications have sufficient data related to safe and effective use in pregnancy. Antibiotics such as
beta-lactams, vancomycin, nitrofurantoin, metronidazole, clindamycin, and fosfomycin are generally
considered safe and effective in pregnancy. Fluoroquinolones and tetracyclines are generally avoided
in pregnancy. Physiologic changes in pregnancy lead to an increase in glomerular filtration rate,
increase in total body volume, and enhanced cardiac output. These changes may lead to pharmacokinetic alterations in antibiotics that require dose adjustment or careful monitoring and assessment.
KEY WORDS antibiotic therapy, pregnancy, teratogenicity, pharmacokinetics.
(Pharmacotherapy 2015;35(11):10521062) doi: 10.1002/phar.1649
Reports suggest that antibiotics account for
nearly 80% of all prescription medications during pregnancy and that approximately 2025%

MM has served on an advisory board for BioCryst Pharmaceuticals.

PBB has served on an advisory board for Durata Therapeutics (now Allergan); PBB has received research funding
from Durata Therapeutics (now Allergan). CMB has served
on an advisory board for Theravance Pharmaceuticals and
Cubist Pharmaceuticals and served on the speakers bureau
for Cubist Pharmaceuticals. KRS has received grant funding
from Astellas Pharma, Inc. LSE, BG have nothing to disclose.
SIDP Insight Paper
*Address for correspondence: Paul Brandon Bookstaver,
Department of Clinical Pharmacy and Outcomes Sciences,
South Carolina College of Pharmacy, University of South
Carolina, 715 Sumter Street, Columbia, SC 29208; e-mail:
bookstaver@sccp.sc.edu.
2015 Pharmacotherapy Publications, Inc.

of women will receive an antibiotic during pregnancy.13 The most common infections encountered during pregnancy include urinary tract
infections (UTIs), including pyelonephritis; sexually transmitted infections (STIs); and upper
respiratory tract infections (URTIs).1 Although
use of any medication during pregnancy is a
risk-versus-benefit decision, untreated infections
such as UTIs or STIs are associated with significant fetal risk including spontaneous abortion,
prematurity, and low birth weight.4, 5 Safety and
efficacy information are not usually available
from randomized controlled trials, as these studies are often not feasible in pregnant women and
are potentially unethical. Thus, pregnancy is
often a standard criterion for exclusion from
clinical trials. It is estimated that only 10% of
medications marketed since 1980 have sufficient
data regarding infantile risk in pregnancy.6

ANTIBIOTICS IN PREGNANCY Bookstaver et al

Antibiotic exposure in pregnancy may have
untoward short-term and long-term effects on
infant weight. A recent study showed that after
adjusting for a number of factors, prenatal exposure of the infant to antimicrobials (via selfreporting by the mother) resulted in a lower
birth weight of approximately 138 g.7 Antimicrobial exposure during pregnancy has recently
been linked to childhood obesity, although
specific antimicrobial class exposure was not
documented in the study.8 Prenatal antibiotic
use and the risk of neurologic disease, including
cerebral palsy and epilepsy, and atopic disease,
including atopic dermatitis and asthma, have
been studied independently. Several studies
demonstrate an association while others do
not.911 One study demonstrated an association
with prenatal antibiotic use and the development
of asthma by age 3 in children at risk for asthma
(odds ratio [OR] 3.1, 95% confidence interval
[CI] 1.46.8).9 There is even less information
known about medication use by trimester and
associated risk. Prenatal antibiotic risk associated with asthma and wheezing was significant
when antibiotics were used by the mother in the
second to third trimesters but not during the
first.9, 12 Conversely, a 2015 Cochrane review of
prophylactic antibiotic use in the second and
third trimesters, which included seven randomized controlled trials, did not demonstrate an
increased risk of congenital abnormality. However, the authors concluded there was insufficient evidence to fully evaluate possible fetal
harm.13
As a method to establish teratogenic potential
of medications, the United States Food and
Drug Administration (FDA) established a pregnancy risk categorization system in 1979.14 This
mandate required newly marketed agents to
include pregnancy risk categories of A, B, C, D,
and X supplemented by general statements for
risk interpretation (Table 1). In December
2014, the FDA approved and unveiled a new
format and content for product labeling, effective June 2015, that abolishes the original FDA
Pregnancy Category system for all prescription
medications approved since June 2001.15 Three
narrative sections required in the product labeling, including Pregnancy, Lactation and
Female and Male Reproductive Potential,
replace previous sections (Figure 1). Specifically, the pregnancy section is divided into
Risk Summary, Clinical Consideration,
Data (human and animal), and Pregnancy
Exposure Registry (if applicable). Labels will

1053

describe detailed information and are required

to be revised when outdated.
In addition to maternal and fetal safety, there
are physiologic changes during pregnancy that
may lead to pharmacokinetic changes and
impact antibiotic therapy.16 Increases in total
body water, blood volume (4050%), and
plasma volume (4050%) contribute to increases
in volume of distribution of various antibiotics.16, 17 Renal blood flow increases by 50%,
possibly due to vasodilation of afferent and efferent arterioles as a result of increased progesterone.16 Serum creatinine decreases, while
glomerular filtration rate (GFR) increases elimination of renally excreted antibiotics. The
patients GFR will approach postpartum values
at approximately 3 weeks prior to delivery.18
Alterations in gastrointestinal motility may lead
to changes in absorption, oral bioavailability,
and delayed onset of action of certain antibiotics.17 There are known changes in hepatic
enzymes during pregnancy that clinicians may
use to adjust doses, but current data are controversial as to whether these changes lead to clinically significant changes in drug metabolism and
subsequent serum concentrations.17, 18 Finally,
decreases in albumin and alterations in maternal
plasma pH are expected to lead to decreased
protein binding and increased concentrations of
unbound drug.16, 17
This concise review provides updated information as of June 2015 on antibiotics in pregnancy, including drug-specific risk evaluation
(Table 2) and clinical utility based on published
evidence.
Aminoglycosides
Amikacin, gentamicin, streptomycin, and
tobramycin are the most commonly prescribed
aminoglycosides. During pregnancy, the serum
half-life of aminoglycosides is shorter and clearance is increased. Due to this and a larger volume of distribution in pregnant women,
aminoglycosides may have a lower serum peak
concentration
compared
to
nonpregnant
women.19 Aminoglycosides cross the placenta
and may result in toxicities, especially if administered in the first trimester of pregnancy.19 Case
reports of irreversible bilateral congenital
deafness with maternal use of streptomycin in
the first trimester have been described, leading
to a boxed warning and FDA Pregnancy Category of D for the class in the United States.1
Other aminoglycosides have not commonly been

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PHARMACOTHERAPY Volume 35, Number 11, 2015

Table 1. Food and Drug Administration Pregnancy Category Ratings with Required Package Labeling Statements Prior to
June 201514
Pregnancy
Category Rating
A

Level of Evidence

Accompanying Text Labeling Requirement

No risk in human studies; Adequate and well-controlled

human studies have failed to demonstrate a risk to the
fetus in the first trimester of pregnancy (and there is
no evidence of risk in later trimesters)
No risk in other studies; Animal reproduction studies
have failed to demonstrate a risk to the fetus and there
are no adequate and well-controlled studies in
pregnant women
Risk not ruled out; Animal reproduction studies have
shown an adverse effect on the fetus and there are no
adequate and well-controlled studies in humans, but
potential benefits may warrant use of the drug in
pregnant women despite potential risks
Positive evidence of risk; There is positive evidence of
human fetal risk based on adverse reaction data from
investigational or marketing experience or studies in
humans, but potential benefits may warrant use of the
drug in pregnant women despite potential risks
Contraindicated in pregnancy; Studies in animals or
humans have demonstrated fetal abnormalities and/or
there is positive evidence of human fetal risk based on
adverse reaction data from investigational or
marketing experience, and the risks involved in use of
the drug in pregnant women clearly outweigh
potential benefits

Labeling Prior to June 2015

8.1 Pregnancy

None

Nevertheless, because the studies in humans

cannot rule out the possibility of harm,
[name of drug] should be used during
pregnancy only if clearly needed
[Name of drug] should be given to a pregnant
woman only if clearly needed

If this drug is used during pregnancy, or if the

patient becomes pregnant while taking this
drug, the patient should be apprised of the
potential hazard to the fetus
[Name of drug] is contraindicated in women
who are or may become pregnant. If this
drug is used during pregnancy, or if the
patient becomes pregnant while taking this
drug, the patient should be apprised of the
potential hazard to the fetus

New Labeling Eecve June 30, 2015

8.1 Pregnancy
(Includes Labor & Delivery)

8.2 Labor and

Delivery

8.2 Lactaon

8.3 Nursing Mothers

8.3 Females and Males

of Reproducve
Potenal

(Includes Nursing Mothers)

Figure 1. Labeling changes for the new pregnancy and lactation section. Adapted from www.fda.gov Available at: http://
www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm093307.htm.

associated with similar hearing loss; however, if

hearing abnormalities did occur, symptoms were
mild without clinical significance.5, 6 Animal
studies with gentamicin in rats and rabbits did
not result in fetal toxicity.1 Traditional or
extended interval dosing of aminoglycosides in
pregnancy are both supported in the literature.20
Despite toxicity reports, short courses of aminoglycosides may be used in pregnant women with
careful monitoring if the likely benefit outweighs
the potential risk. Possible risks should be

explained to the patient, especially in the first

trimester. Due to the risks specifically associated
with streptomycin use, this agent should be
avoided.
Beta-Lactams and Related Antibiotics
Penicillins
Penicillins and their newer derivatives are
the most widely prescribed antimicrobial class

ANTIBIOTICS IN PREGNANCY Bookstaver et al

Table 2. Antibiotic Pregnancy Ratings19,

26

Antibiotic
Aminoglycosides

Beta-lactams and mono-bactams

Penicillins
Including amino-penicillins;
extended-spectrum penicillins;
and beta-lactam/beta-lactamase
inhibitor combinations
Cephalosporins (all generations)
and cephamycinsa
Carbapenems
Doripenem, ertapenem, and meropenem
Imipenem-cilastatin
Aztreonam
Fluoroquinolones
Glycopeptides and lipoglycopeptides
Vancomycin
Lipoglycopeptides
Telavancin, dalbavancin, oritavancin
Macrolides and ketolides
Macrolides
Azithromycin, erythromycin
Clarithromycin
Telithromycin
Oxazolidinones
Linezolid, tedizolid
Tetracyclines
Tetracycline, minocycline, doxycycline
Miscellaneous Antibiotics
Clindamycin

FDA Pregnancy
Category Ratingb

Notes

Streptomycin linked to hearing loss in newborns and

should be avoided, unless specific benefit established.
Short-term use of others in class acceptable with
monitoring, if benefits outweigh the risks

Generally safe to use

Generally safe to use; use ceftriaxone

with caution at term
due to risk of kernicterus

B
C
B
C

Use with caution only when penicillins or

cephalosporins not an option
Use only if severe allergy to beta-lactams
Avoid in pregnancy unless benefits outweigh risks

Appears to be safe and effective

Avoid in pregnancy unless benefits outweigh risks

B
C
C

Generally safe to use azithromycin; use erythromycin and

clarithromycin with caution and only if benefits
outweigh risks
May use if benefits outweigh risks

May use if benefits outweigh risks

Should be avoided

Appears to be safe and effective; review STI guidelines

regarding oral vs vaginal routes
May use if benefits outweigh risks
Limited use, however limited systemic exposure decreases
potential risk to fetus
Appears to be safe and effective
Topical metronidazole should be avoided
Appears to be safe and effective

Daptomycin
Fidaxomicin

B
B

Fosfomycin
Metronidazole
Nitrofurantoin
Polymyxins
Polymyxin B, polymyxin E

B
B
B
C

Should be used with caution. Careful monitoring of

adverse events

Folate antagonists
Sulfamethoxazole, trimethoprim

Avoid trimethoprim and sulfamethoxazole

in first trimester due to major congenital
malformations. Sulfamethoxazole
should be avoided after 32 wks gestation due
to risk of kernicterus
Avoid in pregnancy unless benefits outweigh risks

C
B
C
C

Hepatic enzymes should be monitored closely during

pregnancy while on tuberculosis therapy.
Pyridoxine (B6) should be given with INH
during pregnancy

Tigecycline
Antimycobacterial agents
Isoniazid (INH)
Ethambutol
Pyrazinamide
Rifampin, rifabutin,
rifapentine
Bedaquiline
a

1055

Ceftolozane-tazobactam and ceftazidime-avibactam were recently approved at the time of this manuscript, but also carry a Pregnancy
Category B rating.
b
Pregnancy rating categories were current as of summer of 2015. New guidelines will require a change in pregnancy warning language.

ANTIBIOTICS IN PREGNANCY Bookstaver et al

Table 2. Antibiotic Pregnancy Ratings19,

26

Antibiotic
Aminoglycosides

Beta-lactams and mono-bactams

Penicillins
Including amino-penicillins;
extended-spectrum penicillins;
and beta-lactam/beta-lactamase
inhibitor combinations
Cephalosporins (all generations)
and cephamycinsa
Carbapenems
Doripenem, ertapenem, and meropenem
Imipenem-cilastatin
Aztreonam
Fluoroquinolones
Glycopeptides and lipoglycopeptides
Vancomycin
Lipoglycopeptides
Telavancin, dalbavancin, oritavancin
Macrolides and ketolides
Macrolides
Azithromycin, erythromycin
Clarithromycin
Telithromycin
Oxazolidinones
Linezolid, tedizolid
Tetracyclines
Tetracycline, minocycline, doxycycline
Miscellaneous Antibiotics
Clindamycin

FDA Pregnancy
Category Ratingb

Notes

Streptomycin linked to hearing loss in newborns and

should be avoided, unless specific benefit established.
Short-term use of others in class acceptable with
monitoring, if benefits outweigh the risks

Generally safe to use

Generally safe to use; use ceftriaxone

with caution at term
due to risk of kernicterus

B
C
B
C

Use with caution only when penicillins or

cephalosporins not an option
Use only if severe allergy to beta-lactams
Avoid in pregnancy unless benefits outweigh risks

Appears to be safe and effective

Avoid in pregnancy unless benefits outweigh risks

B
C
C

Generally safe to use azithromycin; use erythromycin and

clarithromycin with caution and only if benefits
outweigh risks
May use if benefits outweigh risks

May use if benefits outweigh risks

Should be avoided

Appears to be safe and effective; review STI guidelines

regarding oral vs vaginal routes
May use if benefits outweigh risks
Limited use, however limited systemic exposure decreases
potential risk to fetus
Appears to be safe and effective
Topical metronidazole should be avoided
Appears to be safe and effective

Daptomycin
Fidaxomicin

B
B

Fosfomycin
Metronidazole
Nitrofurantoin
Polymyxins
Polymyxin B, polymyxin E

B
B
B
C

Should be used with caution. Careful monitoring of

adverse events

Folate antagonists
Sulfamethoxazole, trimethoprim

Avoid trimethoprim and sulfamethoxazole

in first trimester due to major congenital
malformations. Sulfamethoxazole
should be avoided after 32 wks gestation due
to risk of kernicterus
Avoid in pregnancy unless benefits outweigh risks

C
B
C
C

Hepatic enzymes should be monitored closely during

pregnancy while on tuberculosis therapy.
Pyridoxine (B6) should be given with INH
during pregnancy

Tigecycline
Antimycobacterial agents
Isoniazid (INH)
Ethambutol
Pyrazinamide
Rifampin, rifabutin,
rifapentine
Bedaquiline
a

1055

Ceftolozane-tazobactam and ceftazidime-avibactam were recently approved at the time of this manuscript, but also carry a Pregnancy
Category B rating.
b
Pregnancy rating categories were current as of summer of 2015. New guidelines will require a change in pregnancy warning language.

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PHARMACOTHERAPY Volume 35, Number 11, 2015

during pregnancy.1, 2 Intravenous penicillin

from the time of rupture of the placental membranes until delivery remains first-line prophylaxis if the patient is colonized with Group B
Streptococcus, while ampicillin is recommended
as a suitable alternative.21 Penicillins generally
cross the placenta in high concentrations. Penicillins with increased protein binding such as
the anti-staphylococcal penicillins (except methicillin) produce lower fetal tissue concentrations
compared with penicillins such as penicillin G
or ampicillin that have low protein binding.22
Due to increased plasma volume and creatinine
clearance in pregnant women, serum penicillin
concentrations may be decreased by as much as
50%, which may require increased doses and/or
frequency.23
Penicillins have a long track record of safety,
with the parent compound penicillin and the
aminopenicillins (ampicillin and amoxicillin)
having the most robust safety data.5 All penicillins and their derivatives, as well as penicillin
combinations with beta-lactamase inhibitors
such as clavulanate or sulbactam, have been
assigned a Pregnancy Category B rating.19 Pregnant patients with a penicillin allergy diagnosed
with syphilis should undergo desensitization followed by penicillin therapy.

Carbapenems
There is a paucity of data regarding the use of
carbapenems during pregnancy. Ertapenem,
meropenem, and doripenem are Pregnancy Category B, while imipenem-cilastatin is Pregnancy
Category C.19 Pharmacokinetic changes associated with pregnancy have shown decreased imipenem concentrations.19 Carbapenem therapy
should be reserved for pregnant women with
infections that are resistant to penicillin and
cephalosporin therapy with limited alternatives.
Monobactams
While its lack of cross-reactivity with penicillins and cephalosporins makes aztreonam an
appealing choice, there are inconclusive data
regarding its safety in pregnancy. Most safety
data are in the perinatal period, which supports
its Pregnancy Category B rating.19 Aztreonam
should be used with caution during the first trimester as data are limited.27 Due to a lack of
data at this time, aztreonam use should be
restricted to patients with severe penicillin
allergy for whom beta-lactam therapy is contraindicated.
Fluoroquinolones

Cephalosporins and Cephamycins

Cephalosporins have a long history of documented use in pregnancy.1 Cephalosporins remain
a first-line option for many infections in pregnancy
with general use reserved for patients allergic or
intolerant to penicillin therapy. Cephalosporins
have decreased plasma concentrations in pregnant
patients because of increased renal elimination;
therefore, potential dosage and frequency increases
are required.24
All cephalosporins-cephamycins are classified
as Pregnancy Category B.19 Findings from a
Michigan Medicaid database suggested a potential association between ceftriaxone and cardiac
malformation.19 Ceftriaxone remains the drug of
choice for the treatment of gonorrhea during
pregnancy.25 Ceftriaxone should be used cautiously at term due to the potential risk of kernicterus in neonates. Newly approved agents
such as ceftaroline, ceftolozane-tazobactam, and
ceftazidime-avibactam are also Pregnancy Category B agents; however, they should be used
with caution as there is a lack of published data
during pregnancy.26

Although fluoroquinolones are classified as

Pregnancy Category C, they are generally contraindicated in pregnancy.19 They are widely distributed in the body and routes of elimination
differ among the agents.26 Protein binding
ranges from 20% to 50%.26 Fluoroquinolones
may be safe during the first trimester but are not
recommended, as they were associated with fetal
harm in previous animal studies4, 5, 28 There is
a suggested association with fluoroquinolones
and renal toxicity, cardiac defects, and central
nervous system toxicity in the fetus.29, 30 Animal
data have demonstrated bone and cartilage damage in the fetus.19 Data are inconsistent and
more studies are needed to confirm these associations. Authors of a recent literature review concluded that fluoroquinolones may not pose the
same risks to humans as they do to animals
because of weak study designs, small sample
sizes, and confounding variables in the published human studies; however, the data are still
not adequate to support their routine use in
pregnancy.28 Because of the current evidence,
fluoroquinolone use in pregnancy is only recommended if there is no alternative.19, 28

ANTIBIOTICS IN PREGNANCY Bookstaver et al

Glycopeptides and Lipoglycopeptides
Vancomycin is a glycopeptide classified as
Pregnancy Category B and is thought to be safe
for use in pregnancy in the case of serious grampositive infections, particularly during the second and third trimesters.19 Vancomycin is
widely distributed in body tissues, primary eliminated by glomerular filtration in the kidneys,
and 55% protein bound, which may lead to
alterations in kinetics during pregnancy.26 Vancomycin crosses the placenta and has been
found in umbilical cord blood after intravenous
administration.5, 6 Despite the absence of robust
clinical data, there are reports to suggest that
vancomycin is safe to use during pregnancy. In
one report, vancomycin was given to 10 pregnant women for infections caused by methicillin-resistant Staphylococcus aureus (MRSA)
infections.31 No abnormalities, including hearing
loss or nephrotoxicity, were noted in the fetus
after at least 1 week of vancomycin therapy during the second or third trimesters. Other cases,
where vancomycin was administered for 13 and
28 days, produced similar results, with no ototoxicity or nephrotoxicity in the mother or neonate.6 Because there is limited information
available about vancomycin use in the first trimester, caution is warranted during this period.26
In animal trials, no congenital malformations
were noted following intravenous administration
of vancomycin in rats or rabbits given 15 times
the maximum recommended human doses.19, 26
When used orally, vancomycin has little systemic absorption, and is not believed to cause
adverse effects during pregnancy.5, 19
Telavancin, oritavancin, and dalbavancin are
lipoglycopeptides with gram-positive activity
similar to that of vancomycin.26 Similar to vancomycin, telavancin is primarily excreted by the
kidneys. All three are highly protein bound (85
93%) and widely distributed to tissues, which
may mean altered kinetics during pregnancy.26
While there are no human data in pregnancy
available for telavancin, animal data suggest that
telavancin may cause harm (Pregnancy Category
C).19 In rat, rabbit, and minipig studies, telavancin caused limb and skeletal malformations
and fetal weight loss. The manufacturer recommends that women of childbearing potential
have a serum pregnancy test prior to beginning
therapy with telavancin and placed on effective
contraception for the duration of therapy. There
are no human data available for the use of

1057

oritavancin or dalbavancin in pregnancy, and

animal studies found no fetal toxicity at doses
comparable to human doses (Pregnancy Category C).26 With oritavancin, doses of approximately 25% of the human dose showed no
evidence of harm to the fetus in rat and rabbit
studies, while higher doses have not been tested.
After dalbavancin exposures of 3.5 times the
human dose, rats were found to have increased
embryo lethality and offspring death.26 Telavancin, oritavancin, and dalbavancin should be
avoided in pregnancy unless the benefits of
treatment outweigh the risk to the fetus.
Macrolides and Ketolides
Data regarding the safety of macrolides in
pregnancy are widely variable.32 Given the relatively low protein binding, large volumes of distribution, and hepatic metabolism, one would
anticipate that the physiologic changes in pregnancy should have less effect on the kinetics of
these agents.26 The first associations of erythromycin (Pregnancy Category B) exposure
with cardiovascular defects and pyloric stenosis
in offspring occurred in 2003, although later
studies did not corroborate these results.33, 34 In
a retrospective cohort, investigators recorded the
presence of congenital malformations, pyloric
stenosis, or intussusceptions in order to determine the effect of macrolides on fetal development.32 In 1033 women exposed to macrolides
(erythromycin, azithromycin, clarithromycin, or
roxithromycin), there was no association with
the development of major malformation in the
fetus. In addition, exposure in the third trimester was not associated with pyloric stenosis or
intussusception.32 In a review of maternal erythromycin exposure over 15 years, erythromycin
was persistently associated with cardiovascular
defects (risk estimate 1.70; 95% CI 1.262.39).33
Most defects were considered mild. In infants
with congenital heart disease and pyloric stenosis, there was no association with macrolide
exposure compared to nonexposed controls.34
Any product containing erythromycin should be
used with caution in pregnancy and only when
benefit outweighs risk.
Azithromycin has generally been considered
safe for use in pregnancy and is Pregnancy
Category B.19 In rats and mice, azithromycin at
two to four times the human dose was not associated with any evidence of fetal harm.35 In a
comparison of women exposed to azithromycin

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PHARMACOTHERAPY Volume 35, Number 11, 2015

versus other antibiotics or nonteratogens, no differences were found in the rates of major malformations between groups.36 Similar to erythromycin,
data from studies of clarithromycin (Pregnancy
Category C) have been conflicting. In animal
studies, some rats exposed to clarithromycin in
the first trimester did not result in teratogenicity, while other rats showed low incidences of
cardiac abnormalities after clarithromycin exposure.35 Other data report cleft palate in murine
studies and retarded fetal growth in monkeys.35
In clinical reports, including a prospective
controlled study, clarithromycin exposure has
not been associated with increased incidence of
major malformations.23, 37, 38 Although data are
conflicting, it is generally thought that azithromycin is safe to use in pregnancy, while clarithromycin should be used with caution and
only when benefit outweighs risk.
Telithromycin is a ketolide antibacterial with
similar structure and activity as the macrolides.
There are no human data for the use of telithromycin in pregnancy, and it is Pregnancy Category C.26 In rats and rabbits, telithromycin was
not teratogenic at doses ranging from 0.5 to 1.8
times the human doses. At higher doses, delayed
fetal maturation was observed, possibly related
to maternal toxicity. Given its relative limited
utility and potential risks, telithromycin should
be avoided in pregnancy.
Oxazolidinones
Currently, there are a lack of pharmacokinetic
and controlled studies of linezolid and tedizolid
in pregnant women. Linezolid distributes well
into tissue and has 31% protein binding,
whereas tedizolid is highly protein bound (70
90%).26 Positive maternal outcomes without fetal
teratogenesis were detailed in a case report of
4 weeks of linezolid use starting at 14 weeks of
pregnancy.39 Both agents are Pregnancy Category C and animal studies in mice, rats, and rabbits have not shown teratogenic effects.19
However, in rats, linezolid and tedizolid resulted
in mild fetal toxicities, including decreased fetal
body weight and reduced ossification of the
sternebrae at maternally toxic doses.26 A reduction in fetal weight and increase in costal cartilage abnormalities were seen with tedizolid use
in mice with the absence of maternal toxicities
(4-fold increase in the estimated human exposure based on area under the concentration
curve [AUC]).26 Fetal weight loss and maternal
toxicity were identified with tedizolid use in

rabbits. However, in a prenatal and postnatal

toxicity study of rats, no offspring defects were
documented with tedizolid used at the highest
tested dose equivalent to the plasma AUC exposure of the 200 mg/day clinical human dose.26
Oxazolidinones could be considered for use during pregnancy when potential benefits outweigh
the risks.
Tetracyclines
Labeled as Pregnancy Category D, tetracyclines have proven teratogenicity in humans.19
They are associated with congenital defects, with
large doses being linked to maternal liver toxicity.19
In general, tetracyclines penetrate into tissues
and body fluids with the degree of penetration
correlated to lipid solubility (minocycline >
doxycycline > tetracycline).26 Routes of elimination differ by agent and protein binding
widely ranges by agent.26 Tetracyclines cross
the placenta and when used beyond the second
trimester, they can bind to calcium in the
developing fetus and cause permanent discoloration of bones and teeth. They are contraindicated past the fifth week of pregnancy.19
Tetracyclines should be used with extreme caution, if at all, in pregnancy, and only when a
clear benefit has been established. In rare cases,
doxycycline may be considered in pregnant
women who have life-threatening tick-borne illnesses.
Miscellaneous Antibiotics
Clindamycin
Clindamycin is a lincosamide antibiotic,
crosses the placenta, and is classified as Pregnancy Category B.19 Clindamycin is widely distributed into most body tissues and is highly
plasma protein bound (9294%).26 It is excreted
in the urine as 10% active drug and metabolites,
3.6% in the feces, with the remainder excreted
as inactive metabolites.26 A study of 647 newborns that had been exposed to clindamycin in
the first trimester did not support an association
between the drug and congenital defects.19 Evidence is lacking for using oral clindamycin late
in pregnancy. In contrast, vaginal clindamycin is
not recommended due to systemic absorption
(up to 30%), increased risk of adverse neonatal
outcomes (neonatal infection and low birth
weight), and lack of efficacy.19, 25 Late clindamycin use (up to 32 wks gestation) is associated

ANTIBIOTICS IN PREGNANCY Bookstaver et al

with adverse outcomes and the Centers for Disease Control and Prevention Sexually Transmitted
Diseases Treatment Guidelines recommend
avoiding vaginal clindamycin in the latter half
of pregnancy.25, 40
Daptomycin
Daptomycin is Pregnancy Category B.19 It is
highly protein bound (9093%), has a volume of
distribution of 0.1 L/kg, and is primarily excreted
by the kidneys.26 There are no controlled trials
with daptomycin (a cyclic lipopeptide) during
pregnancy. However, isolated reports suggest
that daptomycin may be safe to use.41, 42 In the
first report, a woman in the third trimester was
successfully treated with daptomycin 4 mg/kg
for 14 days for vancomycin- and ampicillinresistant Enterococcus faecium pyelonephritis.41
In another report, a 14-week pregnant patient
with a history of drug abuse was successfully
treated with daptomycin 6 mg/kg for 6 weeks
for tricuspid valve endocarditis.42 No adverse
effects were noted in the patient or in the neonate at birth in either report. In animal studies,
daptomycin was administered to rats and rabbits
at doses 24 times human doses with no evidence of harm to the fetus. Daptomycin should
be used in pregnancy only if the benefit outweighs the risk.
Fidaxomicin
Although fidaxomicin, a nonabsorbable
macrocyclic antibiotic, is Pregnancy Category B,
there are no published documented cases of use
in pregnant women.26 Reproductive studies in
rats and rabbits at doses 66200 times the exposure expected in humans at standard dosing
revealed no harm to the fetus. Systemic exposure
to fidaxomicin is minimal with plasma concentrations falling below the level of detectability in
most patients.43
Fosfomycin
Fosfomycin (Pregnancy Category B) is generally well tolerated, and although it crosses the
placental barrier, no adverse events in the fetus
or infant have been reported.44 In Europe, it is
used with caution in pregnancy as an injectable
agent, which is not available in the United
States44 Oral fosfomycin, for the treatment of
UTIs, may be recommended for use due to its

1059

high sensitivity, ease of use, activity against

multidrug-resistant organisms, and safety in
pregnancy.45
Metronidazole
Metronidazole is classified as Pregnancy Category B; however, it is contraindicated in the first
trimester of pregnancy.19 Several trials have
linked metronidazole use in asymptomatic Trichomonas vaginalis infection or increased fetal
fibronectin concentrations with increased preterm birth (PTB) rates.46, 47 Multivariate analysis
showed no relationship between metronidazole
exposure at any time during pregnancy with
PTB, low birth weight, or congenital abnormalities.48 Vaginal metronidazole should be used
with caution during pregnancy, as a potential
link with congenital hydrocephalus has been
suggested.49 Metronidazole also remains a guideline-recommended therapy for bacterial vaginosis and Trichomonas infections in pregnancy;
however, risk of repeat exposure during pregnancy is unknown and a reduced risk of PTB
has not been clearly established.25
Nitrofurantoin
An antibacterial specific to the urinary tract,
nitrofurantoin is considered Pregnancy Category
B.19 Animals exposed to doses 25 times that of
normal human administration did not result in
teratogenic effects. Because of limited systemic
exposure and its relatively benign adverse effect
profile combined with proven effectiveness,
nitrofurantoin is commonly used in UTI management in pregnant women. A recent meta-analysis
of eight studies did not demonstrate any association of nitrofurantoin exposure in women with
major congenital malformation.50 The meta-analysis did include three case-controlled studies
that revealed a significant increase (OR 1.22; 95%
CI 1.021.45) in malformations, including an
increased risk in hypoplastic left heart (OR
3.07).50 Although not commonly reported, nitrofurantoin may increase the risk of hemolytic
anemia in pregnant patients with severe glucose6-phosphate dehydrogenase deficiency as
indicated by one case report.51 Although there
may be some concern in the recent meta-analysis
requiring further investigation of possible teratogenic effects, nitrofurantoin remains an option
for treatment of UTI and prevention of recurrent UTI in pregnant women.50

1060

PHARMACOTHERAPY Volume 35, Number 11, 2015

Polymyxins

Tigecycline

Polymyxin B and polymyxin E are considered

Pregnancy Category C.19 In the few published
cases and single database examined, there does
not appear to be an increased risk of PTB, low
birth weight or congenital abnormalities,
although the data are quite limited.52 In an animal model examining risk during pregnancy,
polymyxin B demonstrated toxic effects to the
embryo in a dose-dependent manner. This was
hypothesized to be due to its effects on reduction in metabolism, heart loss or neuromuscular
blockade.53 Due to the limited use in pregnant
women and high potential for adverse events,
strong caution is advised prior to use.

Tigecycline is a glycylcycline that crosses the

placenta and is classified as Pregnancy Category
D.19 Animal data have demonstrated adverse
outcomes, including fetal loss in maternal toxic
doses and possible discoloration of infants teeth.
Although no human studies exist to date, this
medication should only be used when the benefit outweighs the risk to the fetus.

Sulfamethoxazole-Trimethoprim
Sulfamethoxazole and trimethoprim are both
rated FDA Pregnancy Category C.19 They are
bound to plasma proteins (sulfamethoxazole >
trimethoprim) and eliminated renally primarily
through glomerular filtration and renal tubular
secretion.26 Animal studies have demonstrated
teratogenic effects. Sulfamethoxazole and
trimethoprim both cross the placenta and should
be avoided in the first trimester due to the
mechanism of trimethoprim as a folate antagonist. Exposure during this period can significantly increase the risk of major congenital
malformations, primarily neural tube and cardiac
defects.54 Trimethoprim has also been associated
with an increase in cleft palates with first trimester use.55 Approximately 2-fold increases in cardiac and limb malformations were seen with
trimethoprim use 12 weeks prior to conception.56 However, maternal folic acid supplementation reduces the risk of major fetal
malformations from trimethoprim. Sulfonamides
should not be used in the third trimester as they
theoretically result in an increase of unbound
bilirubin due to competitive protein binding.
Sulfamethoxazole-trimethoprim use during the
first trimester has been also associated with a
3-fold increase in urinary tract defects and its
use during the last two trimesters has been
associated with small for gestational age newborns.54, 57 Overall, sulfamethoxazole-trimethoprim should be avoided in the first trimester and
after 32 weeks gestation if other treatment
options are available. In the second and third
trimesters, use in pregnant women should be
limited to those situations when the benefits
outweigh the potential risks.

Antimycobacterial Agents
First-line therapy for tuberculosis (TB) in
pregnant women is consistent with the nonpregnant populations and includes isoniazid (INH),
rifampin, ethambutol, and pyrazinamide.58, 59 A
systematic review demonstrated overall safety of
first-line therapy comparable to the general population.59 Of note, many patients were not
exposed to anti-TB medications during the first
trimester, representing the most critical time of
fetal development and risk of abnormalities.
INH, Pregnancy Category C, has not produced
a signal of increased fetal abnormalities in animal
or human data.59, 60 A nonsignificant increase in
hepatitis has been observed in pregnant women
receiving INH, particularly in those with preexisting liver disease and HIV.60 Monitoring of
liver enzymes is important and is recommended
throughout pregnancy.59, 60 An elevation of 35
times the upper limit of normal may prompt
discontinuation of anti-TB therapy. INH is also
recommended for latent TB infection (LTBI) in
pregnancy as a first-line treatment. Low-risk
patients may be advised to defer treatment of
LTBI until after pregnancy because of concerns
about medication exposure. High-risk patients
(e.g., HIV) should be initiated on INH therapy. Pyridoxine (B6) daily oral supplementation (2550 mg/day) is advised in all pregnant
women receiving INH to mitigate neurologic complications in the mother and newborn.59, 60
Rifampin use in animals at up to ten times the
normal human dose did not produce any fetal
abnormalities; however, increasing the dose to
15 times human exposure at the time of conception was associated with significant fetal malformations.60 Use of rifampin in more than 2000
pregnant women has not produced an increase
in fetal abnormalities.60 Rifampin has a Pregnancy Category C rating.19 INH coupled with
rifampin is known to increase liver enzymes
additively; thus, careful monitoring is advised.
An association between rifampin and newborn

ANTIBIOTICS IN PREGNANCY Bookstaver et al

bleeding has been described, so prophylactic
vitamin K may be necessary.60 Data on alternative rifamycinsrifabutin and rifapentineare
limited in pregnancy and should be used with
caution.58 They are considered Pregnancy Category C and not recommended in the current
guidelines.19, 58
Ethambutol is Pregnancy Category B and is
generally considered safe in pregnancy.19, 58 It
is associated with retrobulbar neuritis in the
general population; however, there has not been
an associated increase in either pregnant mothers or infants born to mothers exposed to
ethambutol during pregnancy.60 There are no
controlled studies to date investigating pyrazinamide (PZA) use in pregnant animals or humans,
but literature is available documenting use without fetal or maternal harm.19 PZA may be associated with increased risk of hepatotoxicity,
especially in combination with INH and/or
rifampin. In general, PZA is thought to be safe
in pregnancy (Pregnancy Category C), while
careful risk assessment is needed and enhanced
monitoring, specifically of uric acid and liver
enzymes, is suggested.58
Fluoroquinolones, which may be used in multidrug resistant TB, should be generally avoided
in pregnancy as discussed previously. The risks
and benefits should be weighed in using aminoglycosides in management of TB or other nonMTB infections in pregnancy.58, 59 The newest
anti-TB agent, bedaquiline, is considered Pregnancy Category B.26
Conclusions
The use of antibiotics in pregnancy requires
careful assessment and a discussion of risk versus benefit to mother and fetus, both short and
long term. In general, many antibiotics are considered safe in pregnancy, especially beta-lactams, macrolides, clindamycin, and fosfomycin;
however, additional data are needed for the
majority of antibiotic classes. Emerging antibiotic resistance will certainly play a role in
future use of broad-spectrum and alternative
agents in pregnancy. Pharmacists play a prominent role in risk assessment and evaluation
of available evidence for optimal antibiotic
selection, dosing, duration of therapy, and
monitoring. Pharmacists should also be aware
of the new detailed product labeling for pregnancy that was implemented in the summer of
2015.

1061

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