Drugs in pregnancy

Reviews

Antibiotic Use in Pregnancy and Lactation
What Is and Is Not Known About Teratogenic and Toxic Risks
Gerard G. Nahum, MD, CAPT Kathleen Uhl, USPHS, and CAPT Dianne L. Kennedy, USPHS

OBJECTIVE: Over ten million women are either pregnant icol, ciprofloxacin, doxycycline, levofloxacin, and
or lactating in the United States at any time. The risks of rifampin) to “undetermined” (clindamycin, gentamicin,
medication use for these women are unique. In addition and vancomycin). Assessments were based on “good
to normal physiologic changes that alter the pharmaco- data” (penicillin G and VK), “fair data” (amoxicillin, chlor-
kinetics of drugs, there is the concern of possible terato- amphenicol, ciprofloxacin, doxycycline, levofloxacin, and
genic and toxic effects on the developing fetus and rifampin), “limited data” (clindamycin and gentamicin),
newborn. This article reviews the risks and pharmacoki- and “very limited data” (vancomycin). Significant phar-
netic considerations for 11 broad-spectrum antibiotics macokinetic changes occurred during pregnancy for the
that can be used to treat routine and life-threatening penicillins, fluoroquinolones and gentamicin, indicating
infections during pregnancy and lactation. that dosage adjustments for these drugs may be neces-
sary. With the exception of chloramphenicol, all of these
DATA SOURCES: Information from the U.S. Food and
antibiotics are considered compatible with breastfeed-
Drug Administration (FDA) product labels, the Teratogen
ing.
Information Service, REPROTOX, Shepard’s Catalog of
Teratogenic Agents, Clinical Pharmacology, and the peer- CONCLUSION: Health care professionals should con-
reviewed medical literature was reviewed concerning the sider the teratogenic and toxic risk profiles of antibiotics
use of 11 antibiotics in pregnant and lactating women. to assist in making prescribing decisions for pregnant and
The PubMed search engine was used with the search lactating women. These may become especially impor-
terms “[antibiotic name] and pregnancy,” “[antibiotic tant if anti-infective countermeasures are required to
name] and lactation,” and “[antibiotic name] and breast- protect the health, safety, and survival of individuals
feeding” from January 1940 to November 2005, as well as exposed to pathogenic bacteriologic agents that may
standard reference tracing. occur from bioterrorist acts.
(Obstet Gynecol 2006;107:1120–38)
METHODS OF STUDY SELECTION: One hundred twen-
ty-four references had sufficient information concerning
numbers of subjects, methods, and findings to be in-
cluded.
TABULATION, INTEGRATION, AND RESULTS: The ter-
A ntibiotics are among the most commonly pre-
scribed prescription medications for pregnant
and lactating women.1 More than 10 million women
atogenic potential in humans ranged from “none” (pen- are either pregnant or lactating in the United States at
icillin G and VK) to “unlikely” (amoxicillin, chloramphen- any one time, and they are administered antibiotics
for many reasons.2 Because of the special consider-
From the Department of Obstetrics and Gynecology, Uniformed Services Uni- ations associated with fetal and newborn develop-
versity of the Health Sciences, Bethesda, Maryland; Office of Women’s Health, ment, these women constitute a uniquely vulnerable
U.S. Food and Drug Administration, Rockville, Maryland; FDA Center for
Drug Evaluation and Research, Silver Spring, Maryland.
population for which the risks of medication use must
Presented in part at the FDA Science Forum in Washington, DC, April 27–28,
be separately assessed.
2005. In addition to the pharmacokinetic and pharma-
The views, opinions, interpretations, and conclusions expressed in this article are codynamic changes that may occur during pregnancy
those of the authors only and do not reflect either the policies or positions of the and lactation that can alter the effectiveness of drugs,3
Center for Drug Evaluation and Research, the U.S. Food and Drug Adminis- there is the added concern of the possible teratogenic
tration, or the U.S. Department of Health and Human Services.
and toxic effects that medications may have on the
Corresponding author: Gerard G. Nahum, MD, FACOG, FACS, Box 2184,
Rockville, MD 20847; e-mail: GNahum2003@yahoo.com.
developing fetus and newborn. In general, there is a
© 2006 by The American College of Obstetricians and Gynecologists. Published
dearth of pharmacokinetic and pharmacodynamic
by Lippincott Williams & Wilkins. information regarding the use and proper dosing of
ISSN: 0029-7844/06 Food and Drug Administration (FDA)–approved

1120 VOL. 107, NO. 5, MAY 2006 OBSTETRICS & GYNECOLOGY

drugs in pregnant and lactating women, as well as published by the Centers for Disease Control and
limited data pertaining to the teratogenic potential Prevention in Atlanta.
and the fetal or neonatal toxicity of these marketed
medications. Accordingly, sparse information must RESULTS
sometimes be assembled from diverse sources to A description of the 11 broad-spectrum antibiotics
address these issues. and their general modes of action are provided in
Recently, the threat of bioterrorism has expanded Table 1.
the context in which the potential use of antibiotic All 11 antibiotics cross the placenta and enter the
medications may be needed.4 Although the possibility fetal compartment. For 5 of these, human umbilical
of a large-scale bioterrorist attack in the United States cord blood levels are of the same order of magnitude
is unlikely, the potential for widespread antibiotic use as circulating maternal blood concentrations (chlor-
in this situation emphasizes the need for health care amphenicol, clindamycin, gentamicin, rifampin, and
professionals to be familiar with the risks and benefits vancomycin). For 4, the concentrations are of the
of administering antibiotics to pregnant and lactating same magnitude or higher in amniotic fluid as in
women. maternal blood (ciprofloxacin, clindamycin, levo-
This article reviews the available information floxacin, and vancomycin) (Table 2).
concerning the risks and special circumstances to be All 11 antibiotics are excreted in human breast
considered in pregnant and lactating women for a milk. Limited information concerning the amount in
group of 11 broad-spectrum antibiotics (amoxicillin, breast milk was available for 8 antibiotics (ciprofloxa-
chloramphenicol, ciprofloxacin, clindamycin, doxy- cin, clindamycin, doxycycline, gentamicin, levofloxa-
cin, penicillin G, penicillin VK, and rifampin). No
cycline, gentamicin, levofloxacin, penicillin G, peni-
quantitative data concerning breast milk concentra-
cillin VK, rifampin, and vancomycin). By using this
tions were available for 3 (amoxicillin, chloramphen-
information, better choices can be made for the
icol, and vancomycin) (Table 2).
treatment of different types of bacterial pathogens in
Using the Teratogen Information Service clas-
these particularly vulnerable populations.
sification system for teratogenic risk,44 the terato-
genic potential of the 11 antibiotics during human
DATA SOURCES AND METHODS OF STUDY pregnancy ranged from “none” in 2 cases (penicil-
SELECTION lin G and VK) to “unlikely” in 6 (amoxicillin,
Information from FDA-approved product labels, the chloramphenicol, ciprofloxacin, doxycycline, levo-
Teratogen Information Service, Shepard’s Catalog of floxacin, and rifampin) to “undetermined” in 3
Teratogenic Agents, REPROTOX, Clinical Pharma- (clindamycin, gentamicin, and vancomycin). As-
cology, and the peer-reviewed literature were re- sessments were based on data that were “good” for
viewed for information concerning the use of 11 2 (penicillin G and VK) to “fair” for 6 (amoxicillin,
antibiotics in pregnant and lactating women. The chloramphenicol, ciprofloxacin, doxycycline, levo-
medical literature was queried with the PubMed floxacin, and rifampin) to “limited” for 2 (clinda-
search engine. Papers searched were published from mycin and gentamicin) to “very limited” for 1
January 1940 to November 2005, in any language. (vancomycin). A summary of the human and ani-
The search terms “[antibiotic name] and pregnancy,” mal data contributing to these assessments is shown
“[antibiotic name] and lactation,”, and “[antibiotic in Table 3. The Food and Drug Administration
name] and breastfeeding,” were used, as was standard Pregnancy Category classifications for the 11 anti-
reference tracing. A total of 124 references were biotics (as defined under 21 CFR [Code of Federal
accessed through these sources that contained suffi- Regulations] 201.57 for the A, B, C, D, X Preg-
cient information concerning the numbers of subjects, nancy Category system) (Table 4) were “B” in 5
methods of investigation, and findings to be useful for cases (amoxicillin, clindamycin, penicillin G, peni-
the purpose of drawing conclusions concerning phar- cillin VK, and vancomycin), “C” in 5 cases (chlor-
macokinetic parameters, teratogenic potential, and amphenicol, ciprofloxacin, gentamicin, levofloxa-
toxicity assessments of these drugs. All materials were cin, and rifampin), and “D” in 1 case (doxycycline)
restricted to information from nonproprietary sources (Table 3). In addition to the published literature,
that were available in the public domain. Addition- proprietary data were used to establish the FDA
ally, information concerning the potential treatment pregnancy category for these drugs.
options for exposures and diseases caused by possible Despite numerous concerns regarding the poten-
agents of bioterrorism were obtained from materials tial for maternal and fetal or neonatal toxicity of these

VOL. 107, NO. 5, MAY 2006 Nahum et al Antibiotic Use in Pregnancy 1121

Table 1. Description of the Eleven Broad-Spectrum Antibiotics Investigated
Year of Initial FDA
Antibiotic Description Approval
Amoxicillin Semi-synthetic beta-lactam antibiotic. Inhibits the final stage of 1974
bacterial cell wall synthesis, leading to cell lysis.
Chloramphenicol Broad-spectrum antibiotic isolated from Streptomyces venezuela in 1950
1947, now synthetically available. Binds to the 50S subunit of
bacterial ribosomes, inhibiting peptide bond formation and
protein synthesis.
Ciprofloxacin Fluoroquinolone antibiotic. Exerts its bactericidal effect by 1987
disrupting DNA replication, transcription, recombination, and
repair by inhibiting bacterial DNA gyrase.
Clindamycin Antibiotic derived from lincomycin that has wide-ranging 1970
antimicrobial activity. Binds to the 50S ribosomal subunit,
thereby inhibiting bacterial protein synthesis.
Doxycycline Broad-spectrum antibiotic that binds to the 30S bacterial ribosomal 1967
subunit. Blocks the binding of transfer-RNA to messenger-RNA,
thereby disrupting protein synthesis.
Gentamicin Aminoglycoside antibiotic with broad-spectrum activity. Binds 1966
irreversibly to 30S bacterial ribosomal subunit, thereby inhibiting
protein synthesis.
Levofloxacin Fluoroquinolone antibiotic. L-isomer of ofloxacin, which provides 1996
its principal antibiotic effect. Inhibits bacterial DNA replication,
transcription, recombination, and repair by inhibiting bacterial
type II topoisomerases.
Penicillin G Beta-lactam antibiotic that is primarily bactericidal. Inhibits the 1943
final stage of bacterial cell wall synthesis, leading to cell lysis.
Penicillin V Naturally derived beta-lactam antibiotic. Inhibits the final stage of 1956
(phenoxymethyl bacterial cell wall synthesis, leading to cell lysis. Considered
penicillin) preferable to penicillin G for oral administration because of its
superior gastric acid stability.
Rifampin Rifamycin B derivative that inhibits bacterial and mycobacterial 1971
DNA-dependent RNA polymerase activity. Used primarily for
the treatment of tuberculosis, with additional utility for the
treatment of both leprosy and meningococcal carriers.
Vancomycin Glycopolypeptide antibiotic. Binds to the precursor units of 1964
bacterial cell walls, inhibiting their synthesis and altering cell wall
permeability while also inhibiting RNA synthesis. Because of its
dual mechanism of action, bacterial resistance is rare.
FDA, U.S. Food and Drug Administration.

11 drugs—including idiosyncratic and dose-related lin G, and penicillin VK), lower circulating drug
bone marrow suppression with chloramphenicol, ar- concentrations were measured in pregnant women
thropathies and bone and cartilage damage with than nonpregnant, suggesting that a shorter dosing
ciprofloxacin and levofloxacin, dental staining and interval or increased maternal dose or both may be
hepatic necrosis with doxycycline, and ototoxicity necessary to obtain similar circulating drug concen-
and nephrotoxicity with gentamicin and vancomy- trations as for women in the nonpregnant state. In the
cin—none of these toxicities has been documented case of ciprofloxacin and levofloxacin, circulating
in human mothers or offspring either during preg- concentrations were generally reduced in pregnant
nancy or breastfeeding with these antibiotics (Table women, also suggesting that an increased maternal
3). dose or a shorter dosing interval or both may be
Very limited information was available pertain- necessary. In 3 cases (chloramphenicol, gentamicin,
ing to maternal pharmacokinetics in pregnancy for 8 and vancomycin), therapeutic drug monitoring of
antibiotics (amoxicillin, ciprofloxacin, clindamycin, serum peak and trough levels is recommended to
gentamicin, levofloxacin, penicillin G, penicillin VK, assess circulating drug levels. In 1 case (clindamycin),
and vancomycin), and none was available for 3 the standard pharmacokinetic parameters did not
(chloramphenicol, doxycycline, and rifampin) (Table change appreciably during the first, second, or third
2). For 4 antibiotics (amoxicillin, gentamicin, penicil- trimester of pregnancy (Table 2). Very little pharma-

1122 Nahum et al Antibiotic Use in Pregnancy OBSTETRICS & GYNECOLOGY

Table 2. Current Information for Eleven Broad-Spectrum Antibiotics That May Be Used in Pregnant and Lactating Women
Possible Pregnancy
Dosage/Schedule
Adjustments,
Metabolism, Excretion,
Microbiologic and Recommendations
Antibiotic Spectrum of Activity* Placental Transmission Transmission Into Breast Milk for Monitoring
Amoxicillin Gram-positive aerobes, Crosses the human placenta.5–7 Excreted in human breast milk in small amounts.8 Shorter dosing interval and/
most gram-positive Penicillins transferred to the fetus and amniotic Considered “usually compatible with or increased dose have
anaerobes, gram- fluid reach therapeutic levels.5 breastfeeding.”9† been suggested during
negative aerobes Following therapeutic doses, mean human milk pregnancy to attain similar

VOL. 107, NO. 5, MAY 2006
including some enteric concentrations were 0.1–0.6 ␮g/mL.10 plasma concentrations as
bacilli, Helicobacter, No adverse effects seen in nursing infants whose for nonpregnant
spirochetes, mothers have been treated with amoxicillin. women.6,11
actinomyces* Penicillins are primarily
renally excreted via
tubular secretion and
glomerular filtration.
Volume of distribution
and renal clearance are
increased during the 2nd
13–15
and 3rd trimesters.6,11
Chloramphenicol Gram positives, gram Crosses the human placenta readily. Excreted in human breast milk. Unknown whether dose
negatives, anaerobes, Umbilical cord serum concentrations 29–106% In 5 patients with minor obstetrical lacerations adjustments during
chlamydia, rickettsiae of maternal levels.12 who received 1 g PO qD for 8 days, mean milk pregnancy are necessary.
concentrations were 0.5–2.8 ␮g/mL. In 5 Pharmacokinetics during
patients receiving 2 g PO qD for 8 days for pregnancy has not been
mastitis, mean milk concentrations were 1.8–6.1 specifically studied.
13
␮g/mL. Serum concentrations can
Human milk concentrations are 51–62% of blood be monitored to keep peak
levels.14 and trough levels in the
Percentage of administered dose in human breast ranges of 10–20 and 5–10
15
milk per day is 1.3%. ␮g/mL, respectively. CBC
Effect on breastfed infants considered “unknown monitored to detect bone
but may be of concern.”16 marrow depression.
Ciprofloxacin Gram-negative aerobes, Crosses the human placenta and concentrates in Excreted in human breast milk (Product Circulating fluoroquinolone
17
some staphylococci amniotic fluid (Product information Cipro, information Cipro, 2001). concentrations are lower in
17

Nahum et al
2001). Considered Љusually compatible with pregnant than in
9†
In 20 women at 19–25 weeks of gestation who breastfeeding.” nonpregnant women, but
received two 200-mg IV doses q 12 hours, the In 10 women given 750 mg q12 hours PO, serum no specific
mean amniotic fluid level 2–4 hours after and milk concentrations were obtained 2, 4, 6, pharmacokinetic data is
dosing was 0.12 Ϯ 0.06 ␮g/mL (n ϭ 7; 9, 12, and 24 hours after the 3rd dose. available regarding
amniotic fluid: maternal serum concentration Concentrations were 3.79 Ϯ 1.26, 2.26 Ϯ 0.75, ciprofloxacin in pregnant
[AF:MS ratio] ϭ 0.57), 0.13 Ϯ0.07 ␮g/mL at 0.86 Ϯ 0.27, 0.51 Ϯ 0.18, 0.20 Ϯ 0.05, and women.19 It is unknown
6–8 hours (n ϭ 7; AF:MS ratio ϭ 1.44), and 0.02 Ϯ 0.006 ␮g/mL at these times and the whether dose adjustments
0.10 Ϯ 0.04 ␮g/mL at 10–12 hours (n ϭ 6; AF: ratios of breast milk: serum concentration were during pregnancy are
17
MS ratio ϭ 10.00). 1.84, 2.14, 1.60, 1.70, 1.67, and 0.85, necessary.
17
respectively. For breastfeeding infants Approximately 50–70% of
consuming 150 mL/kg per day, the estimated a dose is excreted in the
maximum dose is 0.569 mg/kg per day or urine and, if renal function
Յ 2.8% the approved dose for infants of is impaired, the serum half-
18
20 mg/kg per day. life is slightly prolonged

Antibiotic Use in Pregnancy
(Product information
Cipro, 2001).
(continued)

1123

Table 2. Current Information for Eleven Broad-Spectrum Antibiotics That May Be Used in Pregnant and Lactating Women (continued)

1124
Possible Pregnancy
Dosage/ Schedule
Adjustments, Metabolism,
Microbiologic Excretion, and
Spectrum of Recommendations for
Antibiotic Activity* Placental Transmission Transmission Into Breast Milk Monitoring

Nahum et al
Clindamycin Gram-positive Crosses the human placenta readily.44,20–23 Excreted in human breast milk (Product Pharmacokinetic parameters do
anaerobes, gram- In 54 women undergoing cesarean delivery who information Clindamycin, 1970). not change during pregnancy
negative anaerobes, received 600 mg IV 30 minutes before surgery, Considered “usually compatible with in women studied during the
aerobic gram-positive umbilical cord blood concentrations were 46% of breastfeeding.”9† 1st, 2nd, and 3rd trimesters of
cocci, streptococci, maternal serum levels.20 At maternal doses of 150 mg orally to 600 mg gestation.20,24 There are no
Clostridia strains After multiple oral doses prior to therapeutic IV, breast milk concentrations range from 0.7 studies to indicate that dosing
abortion, fetal blood concentrations were 25% and to 3.8 ␮g/mL (Product information should be modified during
amniotic fluid levels were 30% of maternal blood Clindamycin, 1970). pregnancy.
levels.21 Cmax and Tmax (after a single
standard dose) and Css (after
multiple doses) do not change
appreciably at any time
during pregnancy.
Doxycycline Gram-positives, gram- Crosses the placenta (Product information Excreted in human breast milk.25 Unknown whether dose

negatives, rickettsiae, Vibramycin, 2001). Use for a short period (1 week) during adjustments during pregnancy
chlamydiae, breastfeeding is considered probably safe.9,16 are necessary.
mycoplasma, Breast milk concentrations are 30–40% of that Pharmacokinetics during
spirochetes, found in maternal blood.25 pregnancy has not been
actinomyces specifically studied.
Enterohepatically recirculated.
Excreted in urine and feces as
unchanged drug. From 29%
to 55.4% of a dose can be
accounted for in the urine by
72 hours (Product information
Vibramycin, 2001).
Gentamicin Gram-negative aerobic Crosses the human placenta.20,26–28 Excreted in human breast milk.29,30 Increased dosage suggested due
rods, many In 2 different studies, peak umbilical cord blood Considered “usually compatible with to decreased serum half-life in
streptococci, levels were 34%26 and 42%20 of associated maternal breastfeeding.”9† pregnancy and lower
Staphylococcus aureus, blood concentrations. Poorly absorbed from the GI tract.29 Only half maternal serum levels.20,31
mycobacteria of nursing newborns had detectable serum In 54 women undergoing
levels, which were low and not likely to cause cesarean delivery, levels were
clinical effects.29 No adverse signs or symptoms lower than nonpregnant
in nursing infants as a result of maternal women.20 Eliminated mainly
treatment.9 by glomerular filtration
Gentamicin, 1966). Clearance
decreased in preeclamptic
patients.32 Dose/ dosing
interval adjusted via peak and
trough levels (Product
information Gentamicin
1966).
(continued)

OBSTETRICS & GYNECOLOGY

Possible Pregnancy
Dosage/ Schedule
Levofloxacin Gram-positives and Crosses the human placenta and concentrates in Excreted in human breast milk in high Circulating fluoroquinolone
gram-negatives amniotic fluid (based on data for racemic concentrations (based on data for racemic concentrations are lower in
ofloxacin) (Product information Levaquin, 1996).17 ofloxacin) (Product information Levaquin, pregnant than in nonpregnant
In 20 women at 19–25 weeks of gestation receiving 1996).17 women, but no specific

VOL. 107, NO. 5, MAY 2006
two IV 400-mg doses of ofloxacin q12 hours, mean Considered “usually compatible with pharmacokinetic data is
amniotic fluid concentration 3–6 hours after dosing breastfeeding.”9† available regarding
was 0.25 Ϯ 0.11 ␮g/mL (n ϭ 6; amniotic fluid: In 10 women given 400 mg of ofloxacin q12 levofloxacin in pregnant
maternal serum concentration [AF:MS ratio] ϭ hours PO, serum and milk concentrations were women.19 There are no data
0.35), 0.15 Ϯ 0.11 ␮g/mL at 6–10 hours (n ϭ 8; obtained 2, 4, 6, 9, 12, and 24 hours after the to support dosing adjustments
AF:MS ratio ϭ 0.67), and 0.13 Ϯ 0.11 ␮g/mL at 3rd dose. Concentrations were 2.41 Ϯ 0.80, during pregnancy.
11–12 hours (n ϭ 6; AF:MS ratio ϭ 2.57).17 1.91 Ϯ 0.64, 1.25 Ϯ 0.42, 0.64 Ϯ 0.21,
0.29 Ϯ 0.10, and 0.05 Ϯ 0.02 ␮g/mL at these
times, with breast milk: serum concentration
ratios of 0.98, 1.30, 1.39, 1.25, 1.12, and 1.66,
respectively.17 For breastfed infants consuming
150 mL/kg per day, the estimated maximum
infant dose of ofloxacin is 0.362 mg/kg per
day.18
Penicillin G Gram-positive aerobes Crosses the human placenta.5,33,34 Excreted in human breast milk in small amounts Shorter dosing interval and/ or
including most Penicillins are transferred to the fetus and amniotic (Product information Bicillin, 2001; product increased dose have been
streptococci/ fluid reaching therapeutic levels.5 information Penicillin V, 1997).15 suggested during pregnancy to
enterococci, gram- Considered “usually compatible with attain similar plasma
positive anaerobes, breastfeeding.”9† concentrations as for
spirochetes, In women with serum concentrations of penicillin nonpregnant women.6,11
actinomyces, some ranging from 6 to 120 ␮g/dL, corresponding Penicillins are primarily renally
gram negatives* breast milk concentrations were 1.2–3.6 ␮g/dL, excreted via tubular secretion
and the amount of the maternal dose appearing and glomerular filtration.
in breast milk per day was estimated at 0.03%.15 Volume of distribution and
renal clearance are increased
during the 2nd and 3rd

Nahum et al
trimesters.6,11
Penicillin VK Gram-positive aerobes Crosses the human placenta readily.5,7,10,33,34,35 Excreted in human breast milk in small amounts Shorter dosing interval and/or
including most Penicillins are transferred to the fetus and amniotic (Product information Penicillin V, 1997).15,36 increased dose have been
streptococci/ fluid reaching therapeutic levels.5 Considered “usually compatible with suggested during pregnancy
enterococci, gram- breastfeeding.”9† to attain similar plasma
positive anaerobes, In 18 women, penicillin V milk concentration concentrations as for
gram negatives depended on presence of mastitis, with peak nonpregnant women.6,11
levels 2.6–5.4 hours after a single PO 1,320-mg Penicillin V is excreted renally,
dose.35 Peak concentration was 30–72 ␮g/dL primarily via tubular
with mean concentration 26-37 ␮g/dL. AUC secretion. Volume of
over 8 hours after dosing was 2.1–3.0 mg-h/L.35 distribution and renal
Estimated dose of penicillin V ingested per day clearance are increased
by breastfed infants is 40–60 ␮g/kg, or 0.09– during the 2nd and 3rd
0.14% of maternal dose per kg body weight.35 trimesters.6,11

(continued)

1125

1126

Nahum et al
Possible Pregnancy
Dosage/ Schedule
Rifampin Mycobacteria, Neisseria Crosses the human placenta (Product information Excreted in human breast milk (Product Unknown whether dosing
meningitidis, S aureus, Rifampin, 1971).37–39 information Rifampin, 1971).15,40,41 adjustments during pregnancy
Haemophilus influenzae, Umbilical cord concentrations between 12% and Considered “usually compatible with are necessary.
Legionella pneumophila, 33% of maternal blood levels, with peak levels breastfeeding.”9† Pharmacokinetics during
Chlamydia occurring concurrently after drug administration.37–39 After a single oral dose of 600 mg, a nursing pregnancy has not been
infant would ingest approximately 0.05% of the specifically studied.
maternal dose per day, or approximately 0.3 Hepatically deacetylated to

mg/day.15,40,41 active metabolite. Parent
compound and metabolites
excreted via biliary
elimination (60%).
Enterohepatic re-circulation;
plasma levels elevated in
hepatic disease. Up to 30%
excreted in urine; renal
clearance is 12% of GFR.38
Vancomycin Gram positives, S aureus, Crosses the human placenta (Product information Excreted in human breast milk when There are no studies to indicate
Staphylococcus Vancomycin, 1964).42,43 administered IV (Product information that vancomycin dosing
epidermidis, Appears in umbilical cord blood after IV maternal Vancomycin, 1964).42 should be modified during
streptococci, treatment (Product information Vancomycin, When administered orally, vancomycin is poorly pregnancy.
enterococci, 1964).42,43 Amniotic fluid and umbilical cord blood absorbed from the GI tract (Product Volume of distribution and
Clostridium, Coryne- concentrations during the early 3rd trimester information Vancomycin, 1964). It is, therefore, plasma clearance both
bacterium comparable to maternal blood levels (fetal-maternal not likely to cause adverse effects in nursing increased, but half-life similar
serum concentration ratio of 0.76).43 infants. to that for nonpregnant
women (4.55 versus 4–6
hours) in a woman
administered IV vancomycin
twice daily from 26–28 weeks
of pregnancy.43
CBC, complete blood count; AF, amniotic fluid; MS, maternal serum; GI, gastrointestinal; AUC, area under the curve; GFR, glomerular filtration rate.
* Listed in the product label and the clinical pharmacology monograph as active against most strains; bacterial resistance occurs commonly in some species of otherwise susceptible
bacteria due to beta-lactamase production.
†
Based on assessment by the American Academy of Pediatrics.


Table 3. Teratogenic and Toxic Potential of Eleven Broad-Spectrum Antibiotics Based on Available Human and Animal Data
Magnitude of Human FDA
Animal Data: Teratogenic Teratogenic Fetal Risk Pregnancy
Antibiotic Human Data: Teratogenic and Toxic Effects and Toxic Fetal Effects (Based on TERIS Assessment)44 Category*
Amoxicillin OR for major congenital anomalies ϭ 1.4 (95% CI 0.9–2.0) for No increased congenital Increased risk of teratogenicity is B
women using amoxicillin ϩ clavulanic acid during malformations in mice treated “unlikely,” based on “fair” data.
pregnancy in a case-control study of 6,935 malformed infants with 3–7 times the maximum
(no increased risk).45 human therapeutic dose of
OR (adjusted) for congenital anomalies ϭ 1.16 (95% CI 0.54– amoxicillin.54
2.50) in a Danish study (1991–2000) of 401 primiparous No adverse reproductive effects

VOL. 107, NO. 5, MAY 2006
women who filled prescriptions for amoxicillin during in rats given amoxicillin-
pregnancy (rate ϭ 4.0%) compared with 10,237 controls who clavulanic acid at doses of 400
did not redeem any prescription drug (rate ϭ 4.1%).46 and 1,200 mg/day prior to
No increased rate of congenital malformations among 147 fertilization and during the
women who received prescriptions for amoxicillin during the first 7 days of gestation
1st trimester.46 (Product information Amoxil,
No increased rate of congenital anomalies among 284 infants 2001).55
whose mothers were administered amoxicillin or ampicillin No adverse fetal effects in pigs
during the 1st trimester, or in 1,060 infants whose mothers given amoxicillin with
were treated at any time during pregnancy.47 clavulanic acid at doses of 600
No significantly increased rate of major or minor anomalies in mg/kg on days 12–42.56
the children of 14 women treated with amoxicillin and Increased frequency of
probenecid during the first 14 weeks of gestation or among embryonic death in mice
57 women treated after the 14th week in a controlled clinical treated with amoxicillin at 6–7
trial on the treatment of gonorrhea during pregnancy.48 times the maximum
No adverse effects in offspring exposed to amoxicillin during therapeutic human dose.54
the 2nd and 3rd trimesters in 3 controlled clinical trials of
antibiotic treatment for premature preterm rupture of
membranes.49–51
An association of necrotizing enterocolitis in newborns and
maternal amoxicillin and clavulanic acid treatment during

Nahum et al
the 3rd trimester was observed in a randomized controlled
trial including 4,826 pregnant patients.52,53
Chloramphenicol OR for major congenital anomalies ϭ 1.7 (95% CI 1.2–2.6) for No increased congenital Increased risk of teratogenicity is C
oral administration at any time during pregnancy in a case- anomalies in monkeys.60 “unlikely,” based on “fair” data.
control study of 22,865 malformed infants (risk marginally No teratogenicity in mice or “Therapeutic doses of chloramphenicol
increased).57 rabbits at 10–40 times the are unlikely to pose a substantial
RR for congenital malformations ϭ 1.19 (95% CI 0.52–2.31) in recommended human dose.61 teratogenic risk.”
348 offspring born to women who took chloramphenicol at No teratogenicity in rats at 2–4
any time during pregnancy (no statistically increased risk).58 times the usual human dose,62
Potential for both dose-related and idiosyncratic bone marrow but various fetal anomalies at
toxicity. Caution should be used near term, during labor, 10–40 times the human
and while breastfeeding due to the possibility of inducing dose.61,63

“gray-baby” syndrome.59 Increased fetal death and
decreased fetal weight in mice,
rats, and rabbits.61–63

1127
(continued)

Table 3. Teratogenic and Toxic Potential of Eleven Broad-Spectrum Antibiotics Based on Available Human and Animal Data (continued)

1128
Ciprofloxacin Congenital malformation rate ϭ 4.0% and spontaneous No detectable adverse effects on Increased risk of teratogenicity is C
abortion rate ϭ 10.7% among liveborns to 56 women who embryonic or fetal “unlikely,” based on “fair” data.

Nahum et al
continued their pregnancies after exposure to ciprofloxacin development in monkeys.69 “Therapeutic doses of ciprofloxacin
(ENTIS registry, 1986–1994). Rates of spontaneous No evidence of teratogenicity in during pregnancy are unlikely to pose
abortion/fetal death, post-natal disorders, prematurity and the offspring of mice, rats, and a substantial teratogenic risk, but the
intra-uterine growth retardation did not exceed background rabbits.70 data are insufficient to state that there
rates.64 is no [increased] risk”.
In a prospective registry of 116 pregnancies exposed to
ciprofloxacin, 91 resulted in live births and 69% of these
were exposed during the 1st trimester. Six liveborns were
malformed (congenital malformation rate ϭ 6.6%). There
was no pattern of minor or major malformations.64
OR for major congenital anomalies ϭ 0.85 (95% CI 0.21–
3.49) in a controlled, prospective, observational study of

200 human pregnancies exposed to fluoroquinolones
during the 1st trimester (2.2% rate versus 2.6% in controls)
[53% ciprofloxacin exposures, with 68% during the 1st
trimester] (no increased risk).65 No clinically significant
musculoskeletal or developmental dysfunctions in
offspring.65
No congenital malformations and no increase in
musculoskeletal problems in offspring of 28 pregnant
women exposed to ciprofloxacin during the 1st trimester.65
Permanent quinolone-induced cartilage or bone damage has
not been documented in humans.66,67 Seven women
exposed to ciprofloxacin during 2nd or 3rd trimester
delivered healthy, normal babies. Motor, adaptive, social,
and language milestones were consistent with age, and
there was no evidence of cartilage damage on regular
clinical assessments up to 5 years of age.68
Clindamycin Major congenital anomalies in 31 of 647 infants (4.8%) whose No increased congenital Increased risk of teratogenicity is B
mothers were given prescriptions for clindamycin during malformations in mice and “undetermined” based on “limited”
the 1st trimester of pregnancy; expected rate 4.3%.71 rats given 1–12 times the data.
No increased rate of congenital malformations in 104 women therapeutic human dose.77,78 “Although a small [increased] risk
treated with clindamycin during the 2nd or 3rd trimester of cannot be excluded, a high risk of
pregnancy for the prevention of preterm delivery.72 congenital anomalies in the children
No increased rate of congenital anomalies in 65 infants born of women treated with clindamycin
to women who received clindamycin and quinine during during pregnancy is unlikely”.
the 2nd or 3rd trimester of pregnancy for the treatment of
malaria.73
(continued)


Clindamycin No congenital malformations among 16 children of women
(continued) treated with clindamycin during the 1st trimester of
pregnancy for attempted prevention of recurrent
miscarriage.74
Can be a causative factor in the development of
pseudomembranous colitis due to overgrowth of Clostridium

VOL. 107, NO. 5, MAY 2006
difficile. Occurs infrequently and no more common among
pregnant women using clindamycin than nonpregnant.75
Has occurred with use of nearly all antibacterial agents,
including clindamycin (Product information Clindamycin,
1970). An infant developed bloody stools after exposure to
clindamycin and gentamicin in breast milk; no blood and
breast milk samples were obtained and a causative
relationship was not established.76
Doxycycline OR for major congenital anomalies ϭ 1.6 (95% CI 1.1–2.3) No increase in congenital Increased risk of teratogenicity is D
for women receiving doxycycline at any time during anomalies in mice treated with “unlikely,” based on “fair” data.
pregnancy in a case-control study of 18,515 infants with 2–6 times the maximum “Therapeutic doses of doxycycline are
congenital abnormalities (risk marginally increased).79 human dose.87 unlikely to pose a substantial risk of
OR of 1.6 was not significantly increased (95% CI 0.8–3.6) for Increased skeletal anomalies and fetal malformations, but the data are
a separately analyzed subgroup exposed during decreased fetal weight in mice insufficient to state that there is no
organogenesis (2–3 months of pregnancy).79 at 17 times the maximum [increased] risk.”
No association of congenital malformations with doxycycline human dose.87 Increased risk of dental staining is
exposure for any of 6 anomalies (cardiovascular defects, No teratogenicity in rabbits “undetermined” based on “very
oral clefts, spina bifida, polydactyly, limb reduction defects, given 2–17 times the limited” data.
and hypospadias) among 1,795 doxycycline-exposed maximum human dose, but
pregnancies in 229,101 completed pregnancies in a decreased fetal weight and
surveillance study of Medicaid recipients.71 increased fetal death at higher

Nahum et al
All mothers reported that exposed infants were normal at 1 doses.87,88
year of age in a prospective study of 81 pregnancies treated No teratogenicity in rats or
with doxycycline for 10 days during the early 1st monkeys at more than 100
trimester.80 times the human dose.89
Tetracycline class antibiotics may induce hepatic necrosis in Delayed long bone skeletal
some pregnant women.81–83 differentiation in albino rats
Some tetracyclines can cause cosmetic staining of primary given 8 mg/kg of doxycycline
dentition for exposures during the 2nd or 3rd trimester,84,85 intraperitoneally from
and there is some concern about possible enamel gestational day 8 to 19.90
hypoplasia and reversible depression of fetal bone growth.86 Delayed appearance of
No staining from doxycycline has been documented in primary ossification centers in
humans. the humerus, ulna, radius,

femur, tibia, and fibula
compared with controls
(P Ͻ .001).90

1129
(continued)


1130
Gentamicin OR for major congenital anomalies ϭ 1.7 (95% CI 0.9–3.2), Mice given 1–12 times the Increased risk of teratogenicity is C
in a case-control study of 22,865 infants with congenital maximum human dose had a “undetermined” based on “limited”

Nahum et al
anomalies (no increased risk); included 19 critical slight statistically data.
exposures, with the majority occurring during the 2nd or nonsignificant increase in the “A small [increased] risk cannot be
3rd month of pregnancy.91 rate of congenital anomalies at excluded, but there is no indication
A randomized trial of 3 parenteral antibiotic regimens showed lower doses, but not higher that the risk of malformations in
no congenital abnormalities among 57 infants whose ones.95 Fetal deaths were children of women treated with
mothers were treated with gentamicin during the 1st or 2nd increased.95 gentamicin during pregnancy is likely
trimesters.92 In mice treated with 11–18 times to be great.”
The frequency of newborn hearing screening failures was not the maximum human dose,
different between 46 infants whose mothers were treated dose-dependent ultrastructural
with gentamicin during pregnancy and 92 unexposed vestibular system damage was
control infants.93 demonstrated in offspring.96
Renal cystic dysplasia was reported in a child whose mother In rats treated systemically with

was given gentamicin during the 7th week of pregnancy.94 daily doses up to 500 times
There is no proof of a causal relationship between the the maximum human
gentamicin treatment and the nephrotoxicity, but it cannot ophthalmic dose, gentamicin
be excluded.94 depressed median glomerular
No ototoxicity or nephrotoxicity has been documented in counts and kidney and body
human fetuses.44 weights in newborns (Product
information Gentamicin,
1966).
Rats given 9–25 times the
maximum human dose had
nephrotoxicity in offspring of
type typically expected from
aminoglycoside exposure.97
Levofloxacin No well-controlled studies of the safety and efficacy of No teratogenicity in rats at oral There are no well-controlled studies of C
levofloxacin in pregnant or lactating women have been doses up to 810 mg/kg per the safety and efficacy of levofloxacin
reported. day (9.4 times the maximum in pregnant or lactating women.
human dose based on BSA) or Comprehensive reviews of published
IV doses up to 160 mg/kg per data concerning norfloxacin and
day (1.9 times the maximum ciprofloxacin (2 related
human dose) (Product fluoroquinolone antibiotics) conclude
information Levaquin, 1996). that an increased risk of teratogenicity
is “unlikely” based on “fair” data.
(continued)


Levofloxacin No teratogenicity or adverse
(continued) effects on fertility in rats at
oral doses up to 360 mg/kg
per day.91 Decreased fetal
body weight and increased
fetal mortality in rats given

VOL. 107, NO. 5, MAY 2006
810 mg/kg per day, with
retardation of fetal skeletal
ossification/skeletal variations
Levaquin, 1996).98
No teratogenicity in rabbits
given up to 50 mg/kg per day
orally (1.1 times the maximum
recommended human dose
based on BSA), or IV at doses
up to 25 mg/kg per day (0.5
times the highest
recommended human dose)
Levaquin, 1996).98
Penicillin G OR for major congenital anomalies ϭ 1.3 (95% CI 1.1–1.5) No teratogenicity in mice Increased risk of teratogenicity is “none” B
for women who used penicillin G during pregnancy in a administered up to 500 units/g based on “good” data.
case-control study (1980-1996) of 22,865 malformed infants on gestation day 14.103
(marginally increased risk suggested attributable to recall No teratogenicity or increased
bias by the authors).99 abortions in rabbits
RR for congenital malformations ϭ 0.92 (95% CI 0.78–1.10) maintained on 100 mg/kg per

Nahum et al
among 7,171 infants whose mothers were treated with a day during pregnancy.104
penicillin derivative at any time during pregnancy (no No teratogenicity or impaired
increased risk).58 fertility in mice, rats and
The frequency of 1st-trimester penicillin use was no greater rabbits (Product information
than expected in a prospective study of 194 infants with Bicillin, 2001).
major malformations born in Sweden (1963–1965).100
OR for neural tube defects ϭ 0.90 (95% CI 0.37–2.17). Rate
of 1st-trimester penicillin use was no greater than expected
in a case-control study of 538 infants with neural tube
defects and 539 controls in California from 1989 to 1991
(no increased risk).101
No adverse effects noted in offspring despite widespread use

of penicillins during pregnancy.10,44,58,99,102
(continued)

1131


1132
Penicillin VK OR for congenital anomalies ϭ 1.25 (95% CI 0.84–1.86) (not No evidence of impaired fertility Increased risk of teratogenicity is “none” B
increased) among 654 users of penicillin VK with or without or harm to the fetus due to based on “good” data.

Nahum et al
other drug use during the 1st trimester (1991–1998). The rate penicillin in reproduction
of congenital anomalies (4.6%) was no greater than for 9,263 studies in mouse, rat, and
controls who did not redeem any prescription drug during rabbit (Product information
pregnancy (3.6%).105 Nine cardiovascular abnormalities Penicillin V, 1997).
occurred in the group exposed to penicillin VK (OR 1.74;
95% CI 0.83–3.65) (not statistically increased).105
OR for congenital anomalies ϭ 1.3 (95% CI 1.1–1.6) in a case-
control study (1980–1996) of 22,865 infants with congenital
anomalies (173 [0.8%] treated with penicillin V during
pregnancy). Adjusted OR for medically documented penicillin
V use during the 1st trimester showed no significant
association between maternal exposure and congenital

anomalies.106
Rifampin In a meta-analysis of case reports (1971–1977; 15 different No increased rate of congenital Increased risk of teratogenicity is “unlikely” C
authors),111 congenital malformations among 410 offspring in anomalies in rats or mice based on “limited to fair” data.
442 gravidas treated with rifampin—usually in combination treated with 2.5–10 times the “The data are insufficient to state that there
with other drugs—was 3.3% and no higher than expected for usual human dose.112 is no [increased] risk”.
human populations.44,107 Exposure was during the first 4 In rats and mice treated
months in 109 cases. The spontaneous abortion rate ϭ 1.7% with Ն 15 times the human
was below expected for a general obstetrical population.108 dose (Ն 150 mg/kg per day),
In 226 women exposed during 229 conceptions, 9 offspring had there was an increased rate of
congenital malformations among 207 births (4.3%)37,109; this spina bifida, cleft palate, and
was no greater than the historical rate for women afflicted nonossified skeletal elements
with tuberculosis.37,109 The spontaneous abortion rate ϭ 2.4% (Product information
and was below expected for general obstetric populations.108 Rifampin, 1971).37,109 The
No congenital anomalies in the offspring of 13 women treated malformation rate was dose-
with rifampin for leprosy,110 or 18 women treated for dependent. No increase in rate
brucellosis.111 Treatment occurred during all trimesters. of congenital anomalies in
rabbits treated with similar
doses (200 mg/kg per day).
No fetal malformations in rabbits
administered doses of 50 mg/
kg per day for 20 days
beginning on day 2.113
In rabbits given doses of up to
20 times the usual human
dose, imperfect osteogenesis
and embryotoxicity were
reported (Product information
Rifampin, 1971).

(continued)

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