Reviews

Antibiotic Use in Pregnancy and LactationWhat 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 pregnantor lactating in the United States at any time. The risks ofmedication use for these women are unique. In additionto normal physiologic changes that alter the pharmaco-kinetics of drugs, there is the concern of possible terato-genic and toxic effects on the developing fetus andnewborn. This article reviews the risks and pharmacoki-netic considerations for 11 broad-spectrum antibioticsthat can be used to treat routine and life-threateninginfections during pregnancy and lactation.

DATA SOURCES: Information from the U.S. Food andDrug Administration (FDA) product labels, the TeratogenInformation Service, REPROTOX, Shepard’s Catalog ofTeratogenic Agents, Clinical Pharmacology, and the peer-reviewed medical literature was reviewed concerning theuse of 11 antibiotics in pregnant and lactating women.The PubMed search engine was used with the searchterms “[antibiotic name] and pregnancy,” “[antibioticname] and lactation,” and “[antibiotic name] and breast-feeding” from January 1940 to November 2005, as well asstandard reference tracing.

METHODS OF STUDY SELECTION: One hundred twen-ty-four references had sufficient information concerningnumbers of subjects, methods, and findings to be in-cluded.

TABULATION, INTEGRATION, AND RESULTS: The ter-atogenic potential in humans ranged from “none” (pen-icillin G and VK) to “unlikely” (amoxicillin, chloramphen-

icol, ciprofloxacin, doxycycline, levofloxacin, andrifampin) to “undetermined” (clindamycin, gentamicin,and vancomycin). Assessments were based on “gooddata” (penicillin G and VK), “fair data” (amoxicillin, chlor-amphenicol, ciprofloxacin, doxycycline, levofloxacin, andrifampin), “limited data” (clindamycin and gentamicin),and “very limited data” (vancomycin). Significant phar-macokinetic changes occurred during pregnancy for thepenicillins, fluoroquinolones and gentamicin, indicatingthat dosage adjustments for these drugs may be neces-sary. With the exception of chloramphenicol, all of theseantibiotics are considered compatible with breastfeed-ing.

CONCLUSION: Health care professionals should con-sider the teratogenic and toxic risk profiles of antibioticsto assist in making prescribing decisions for pregnant andlactating women. These may become especially impor-tant if anti-infective countermeasures are required toprotect the health, safety, and survival of individualsexposed to pathogenic bacteriologic agents that mayoccur from bioterrorist acts.(Obstet Gynecol 2006;107:1120–38)

Antibiotics are among the most commonly pre-scribed prescription medications for pregnant

and lactating women.1 More than 10 million womenare either pregnant or lactating in the United States atany one time, and they are administered antibioticsfor many reasons.2 Because of the special consider-ations associated with fetal and newborn develop-ment, these women constitute a uniquely vulnerablepopulation for which the risks of medication use mustbe separately assessed.

In addition to the pharmacokinetic and pharma-codynamic changes that may occur during pregnancyand lactation that can alter the effectiveness of drugs,3

there is the added concern of the possible teratogenicand toxic effects that medications may have on thedeveloping fetus and newborn. In general, there is adearth of pharmacokinetic and pharmacodynamicinformation regarding the use and proper dosing ofFood and Drug Administration (FDA)–approved

From the Department of Obstetrics and Gynecology, Uniformed Services Uni-versity of the Health Sciences, Bethesda, Maryland; Office of Women’s Health,U.S. Food and Drug Administration, Rockville, Maryland; FDA Center forDrug Evaluation and Research, Silver Spring, Maryland.

Presented in part at the FDA Science Forum in Washington, DC, April 27–28,2005.

The views, opinions, interpretations, and conclusions expressed in this article arethose of the authors only and do not reflect either the policies or positions of theCenter for Drug Evaluation and Research, the U.S. Food and Drug Adminis-tration, or the U.S. Department of Health and Human Services.

Corresponding author: Gerard G. Nahum, MD, FACOG, FACS, Box 2184,Rockville, MD 20847; e-mail: GNahum2003@yahoo.com.

© 2006 by The American College of Obstetricians and Gynecologists. Publishedby Lippincott Williams & Wilkins.ISSN: 0029-7844/06

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

drugs in pregnant and lactating women, as well aslimited data pertaining to the teratogenic potentialand the fetal or neonatal toxicity of these marketedmedications. Accordingly, sparse information mustsometimes be assembled from diverse sources toaddress these issues.

Recently, the threat of bioterrorism has expandedthe context in which the potential use of antibioticmedications may be needed.4 Although the possibilityof a large-scale bioterrorist attack in the United Statesis unlikely, the potential for widespread antibiotic usein this situation emphasizes the need for health careprofessionals to be familiar with the risks and benefitsof administering antibiotics to pregnant and lactatingwomen.

This article reviews the available informationconcerning the risks and special circumstances to beconsidered in pregnant and lactating women for agroup of 11 broad-spectrum antibiotics (amoxicillin,chloramphenicol, ciprofloxacin, clindamycin, doxy-cycline, gentamicin, levofloxacin, penicillin G, peni-cillin VK, rifampin, and vancomycin). By using thisinformation, better choices can be made for thetreatment of different types of bacterial pathogens inthese particularly vulnerable populations.

DATA SOURCES AND METHODS OF STUDYSELECTIONInformation from FDA-approved product labels, theTeratogen Information Service, Shepard’s Catalog ofTeratogenic Agents, REPROTOX, Clinical Pharma-cology, and the peer-reviewed literature were re-viewed for information concerning the use of 11antibiotics in pregnant and lactating women. Themedical literature was queried with the PubMedsearch engine. Papers searched were published fromJanuary 1940 to November 2005, in any language.The search terms “[antibiotic name] and pregnancy,”“[antibiotic name] and lactation,”, and “[antibioticname] and breastfeeding,” were used, as was standardreference tracing. A total of 124 references wereaccessed through these sources that contained suffi-cient information concerning the numbers of subjects,methods of investigation, and findings to be useful forthe purpose of drawing conclusions concerning phar-macokinetic parameters, teratogenic potential, andtoxicity assessments of these drugs. All materials wererestricted to information from nonproprietary sourcesthat were available in the public domain. Addition-ally, information concerning the potential treatmentoptions for exposures and diseases caused by possibleagents of bioterrorism were obtained from materials

published by the Centers for Disease Control andPrevention in Atlanta.

RESULTSA description of the 11 broad-spectrum antibioticsand their general modes of action are provided inTable 1.

All 11 antibiotics cross the placenta and enter thefetal compartment. For 5 of these, human umbilicalcord blood levels are of the same order of magnitudeas circulating maternal blood concentrations (chlor-amphenicol, clindamycin, gentamicin, rifampin, andvancomycin). For 4, the concentrations are of thesame magnitude or higher in amniotic fluid as inmaternal blood (ciprofloxacin, clindamycin, levo-floxacin, and vancomycin) (Table 2).

All 11 antibiotics are excreted in human breastmilk. Limited information concerning the amount inbreast milk was available for 8 antibiotics (ciprofloxa-cin, clindamycin, doxycycline, gentamicin, levofloxa-cin, penicillin G, penicillin VK, and rifampin). Noquantitative data concerning breast milk concentra-tions were available for 3 (amoxicillin, chloramphen-icol, and vancomycin) (Table 2).

Using the Teratogen Information Service clas-sification system for teratogenic risk,44 the terato-genic potential of the 11 antibiotics during humanpregnancy ranged from “none” in 2 cases (penicil-lin G and VK) to “unlikely” in 6 (amoxicillin,chloramphenicol, ciprofloxacin, doxycycline, levo-floxacin, and rifampin) to “undetermined” in 3(clindamycin, gentamicin, and vancomycin). As-sessments were based on data that were “good” for2 (penicillin G and VK) to “fair” for 6 (amoxicillin,chloramphenicol, ciprofloxacin, doxycycline, levo-floxacin, and rifampin) to “limited” for 2 (clinda-mycin and gentamicin) to “very limited” for 1(vancomycin). A summary of the human and ani-mal data contributing to these assessments is shownin Table 3. The Food and Drug AdministrationPregnancy Category classifications for the 11 anti-biotics (as defined under 21 CFR [Code of FederalRegulations] 201.57 for the A, B, C, D, X Preg-nancy Category system) (Table 4) were “B” in 5cases (amoxicillin, clindamycin, penicillin G, peni-cillin VK, and vancomycin), “C” in 5 cases (chlor-amphenicol, ciprofloxacin, gentamicin, levofloxa-cin, and rifampin), and “D” in 1 case (doxycycline)(Table 3). In addition to the published literature,proprietary data were used to establish the FDApregnancy category for these drugs.

Despite numerous concerns regarding the poten-tial for maternal and fetal or neonatal toxicity of these

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

11 drugs—including idiosyncratic and dose-relatedbone marrow suppression with chloramphenicol, ar-thropathies and bone and cartilage damage withciprofloxacin and levofloxacin, dental staining andhepatic necrosis with doxycycline, and ototoxicityand nephrotoxicity with gentamicin and vancomy-cin—none of these toxicities has been documentedin human mothers or offspring either during preg-nancy or breastfeeding with these antibiotics (Table3).

Very limited information was available pertain-ing to maternal pharmacokinetics in pregnancy for 8antibiotics (amoxicillin, ciprofloxacin, clindamycin,gentamicin, levofloxacin, penicillin G, penicillin VK,and vancomycin), and none was available for 3(chloramphenicol, doxycycline, and rifampin) (Table2). For 4 antibiotics (amoxicillin, gentamicin, penicil-

lin G, and penicillin VK), lower circulating drugconcentrations were measured in pregnant womenthan nonpregnant, suggesting that a shorter dosinginterval or increased maternal dose or both may benecessary to obtain similar circulating drug concen-trations as for women in the nonpregnant state. In thecase of ciprofloxacin and levofloxacin, circulatingconcentrations were generally reduced in pregnantwomen, also suggesting that an increased maternaldose or a shorter dosing interval or both may benecessary. In 3 cases (chloramphenicol, gentamicin,and vancomycin), therapeutic drug monitoring ofserum peak and trough levels is recommended toassess circulating drug levels. In 1 case (clindamycin),the standard pharmacokinetic parameters did notchange appreciably during the first, second, or thirdtrimester of pregnancy (Table 2). Very little pharma-

Table 1. Description of the Eleven Broad-Spectrum Antibiotics Investigated

Antibiotic DescriptionYear of Initial FDA

Approval

Amoxicillin Semi-synthetic beta-lactam antibiotic. Inhibits the final stage ofbacterial cell wall synthesis, leading to cell lysis.

1974

Chloramphenicol Broad-spectrum antibiotic isolated from Streptomyces venezuela in1947, now synthetically available. Binds to the 50S subunit ofbacterial ribosomes, inhibiting peptide bond formation andprotein synthesis.

1950

Ciprofloxacin Fluoroquinolone antibiotic. Exerts its bactericidal effect bydisrupting DNA replication, transcription, recombination, andrepair by inhibiting bacterial DNA gyrase.

1987

Clindamycin Antibiotic derived from lincomycin that has wide-rangingantimicrobial activity. Binds to the 50S ribosomal subunit,thereby inhibiting bacterial protein synthesis.

1970

Doxycycline Broad-spectrum antibiotic that binds to the 30S bacterial ribosomalsubunit. Blocks the binding of transfer-RNA to messenger-RNA,thereby disrupting protein synthesis.

1967

Gentamicin Aminoglycoside antibiotic with broad-spectrum activity. Bindsirreversibly to 30S bacterial ribosomal subunit, thereby inhibitingprotein synthesis.

1966

Levofloxacin Fluoroquinolone antibiotic. L-isomer of ofloxacin, which providesits principal antibiotic effect. Inhibits bacterial DNA replication,transcription, recombination, and repair by inhibiting bacterialtype II topoisomerases.

1996

Penicillin G Beta-lactam antibiotic that is primarily bactericidal. Inhibits thefinal stage of bacterial cell wall synthesis, leading to cell lysis.

1943

Penicillin V(phenoxymethylpenicillin)

Naturally derived beta-lactam antibiotic. Inhibits the final stage ofbacterial cell wall synthesis, leading to cell lysis. Consideredpreferable to penicillin G for oral administration because of itssuperior gastric acid stability.

1956

Rifampin Rifamycin B derivative that inhibits bacterial and mycobacterialDNA-dependent RNA polymerase activity. Used primarily forthe treatment of tuberculosis, with additional utility for thetreatment of both leprosy and meningococcal carriers.

1971

Vancomycin Glycopolypeptide antibiotic. Binds to the precursor units ofbacterial cell walls, inhibiting their synthesis and altering cell wallpermeability while also inhibiting RNA synthesis. Because of itsdual mechanism of action, bacterial resistance is rare.

1964

FDA, U.S. Food and Drug Administration.

1122 Nahum et al Antibiotic Use in Pregnancy OBSTETRICS & GYNECOLOGY

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VOL. 107, NO. 5, MAY 2006 Nahum et al Antibiotic Use in Pregnancy 1123

Tabl

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stfe

edin

gis

cons

ider

edpr

obab

lysa

fe.9,

16

Bre

ast

milk

conc

entr

atio

nsar

e30

–40%

ofth

atfo

und

inm

ater

nalb

lood

.25

Unk

now

nw

heth

erdo

sead

just

men

tsdu

ring

preg

nanc

yar

ene

cess

ary.

Phar

mac

okin

etic

sdu

ring

preg

nanc

yha

sno

tbe

ensp

ecifi

cally

stud

ied.

Ent

eroh

epat

ical

lyre

circ

ulat

ed.

Exc

rete

din

urin

ean

dfe

ces

asun

chan

ged

drug

.Fro

m29

%to

55.4

%of

ado

seca

nbe

acco

unte

dfo

rin

the

urin

eby

72ho

urs

(Pro

duct

info

rmat

ion

Vib

ram

ycin

,200

1).

Gen

tam

icin

Gra

m-n

egat

ive

aero

bic

rods

,man

yst

rept

ococ

ci,

Stap

hylo

cocc

usau

reus

,m

ycob

acte

ria

Cro

sses

the

hum

anpl

acen

ta.20

,26–

28

In2

diffe

rent

stud

ies,

peak

umbi

lical

cord

bloo

dle

vels

wer

e34

%26

and

42%

20of

asso

ciat

edm

ater

nal

bloo

dco

ncen

trat

ions

.

Exc

rete

din

hum

anbr

east

milk

.29,3

0

Con

side

red

“usu

ally

com

patib

lew

ithbr

east

feed

ing.

”9†

Poor

lyab

sorb

edfr

omth

eG

Itr

act.29

Onl

yha

lfof

nurs

ing

new

born

sha

dde

tect

able

seru

mle

vels

,whi

chw

ere

low

and

not

likel

yto

caus

ecl

inic

alef

fect

s.29

No

adve

rse

sign

sor

sym

ptom

sin

nurs

ing

infa

nts

asa

resu

ltof

mat

erna

ltr

eatm

ent.9

Incr

ease

ddo

sage

sugg

este

ddu

eto

decr

ease

dse

rum

half-

life

inpr

egna

ncy

and

low

erm

ater

nal

seru

mle

vels

.20,3

1

In54

wom

enun

derg

oing

cesa

rean

deliv

ery,

leve

lsw

ere

low

erth

anno

npre

gnan

tw

omen

.20E

limin

ated

mai

nly

bygl

omer

ular

filtr

atio

n(P

rodu

ctin

form

atio

nG

enta

mic

in,1

966)

.C

lear

ance

decr

ease

din

pree

clam

ptic

patie

nts.

32D

ose/

dosi

ngin

terv

alad

just

edvi

ape

akan

dtr

ough

leve

ls(P

rodu

ctin

form

atio

nG

enta

mic

in19

66).

(con

tinue

d)

1124 Nahum et al Antibiotic Use in Pregnancy OBSTETRICS & GYNECOLOGY

Tabl

e2.

Cur

rent

Info

rmat

ion

for

Elev

enB

road

-Sp

ectr

umA

ntib

ioti

csTh

atM

ayB

eU

sed

inPr

egna

ntan

dLa

ctat

ing

Wo

men

(co

ntin

ued

)

Ant

ibio

tic

Mic

rob

iolo

gic

Spec

trum

of

Act

ivit

y*Pl

acen

tal

Tran

smis

sio

nTr

ansm

issi

on

Into

Bre

ast

Milk

Poss

ible

Preg

nanc

yD

osa

ge/

Sche

dul

eA

dju

stm

ents

,M

etab

olis

m,

Excr

etio

n,an

dR

eco

mm

end

atio

nsfo

rM

oni

tori

ng

Lev

oflo

xaci

nG

ram

-pos

itive

san

dgr

am-n

egat

ives

Cro

sses

the

hum

anpl

acen

taan

dco

ncen

trat

esin

amni

otic

fluid

(bas

edon

data

for

race

mic

oflo

xaci

n)(P

rodu

ctin

form

atio

nL

evaq

uin,

1996

).17

In20

wom

enat

19–2

5w

eeks

ofge

stat

ion

rece

ivin

gtw

oIV

400-

mg

dose

sof

oflo

xaci

nq1

2ho

urs,

mea

nam

niot

icflu

idco

ncen

trat

ion

3–6

hour

saf

ter

dosi

ngw

as0.

25�

0.11

�g/

mL

(n�

6;am

niot

icflu

id:

mat

erna

lser

umco

ncen

trat

ion

[AF:

MS

ratio

]�

0.35

),0.

15�

0.11

�g/

mL

at6–

10ho

urs

(n�

8;A

F:M

Sra

tio�

0.67

),an

d0.

13�

0.11

�g/

mL

at11

–12

hour

s(n

�6;

AF:

MS

ratio

�2.

57).17

Exc

rete

din

hum

anbr

east

milk

inhi

ghco

ncen

trat

ions

(bas

edon

data

for

race

mic

oflo

xaci

n)(P

rodu

ctin

form

atio

nL

evaq

uin,

1996

).17

Con

side

red

“usu

ally

com

patib

lew

ithbr

east

feed

ing.

”9†

In10

wom

engi

ven

400

mg

ofof

loxa

cin

q12

hour

sPO

,ser

uman

dm

ilkco

ncen

trat

ions

wer

eob

tain

ed2,

4,6,

9,12

,and

24ho

urs

afte

rth

e3r

ddo

se.C

once

ntra

tions

wer

e2.

41�

0.80

,1.

91�

0.64

,1.2

5�

0.42

,0.6

4�

0.21

,0.

29�

0.10

,and

0.05

�0.

02�

g/m

Lat

thes

etim

es,w

ithbr

east

milk

:se

rum

conc

entr

atio

nra

tios

of0.

98,1

.30,

1.39

,1.2

5,1.

12,a

nd1.

66,

resp

ectiv

ely.

17Fo

rbr

east

fed

infa

nts

cons

umin

g15

0m

L/k

gpe

rda

y,th

ees

timat

edm

axim

umin

fant

dose

ofof

loxa

cin

is0.

362

mg/

kgpe

rda

y.18

Cir

cula

ting

fluor

oqui

nolo

neco

ncen

trat

ions

are

low

erin

preg

nant

than

inno

npre

gnan

tw

omen

,but

nosp

ecifi

cph

arm

acok

inet

icda

tais

avai

labl

ere

gard

ing

levo

floxa

cin

inpr

egna

ntw

omen

.19T

here

are

noda

tato

supp

ort

dosi

ngad

just

men

tsdu

ring

preg

nanc

y.

Peni

cilli

nG

Gra

m-p

ositi

veae

robe

sin

clud

ing

mos

tst

rept

ococ

ci/

ente

roco

cci,

gram

-po

sitiv

ean

aero

bes,

spir

oche

tes,

actin

omyc

es,s

ome

gram

nega

tives

*

Cro

sses

the

hum

anpl

acen

ta.5,

33,3

4

Peni

cilli

nsar

etr

ansf

erre

dto

the

fetu

san

dam

niot

icflu

idre

achi

ngth

erap

eutic

leve

ls.5

Exc

rete

din

hum

anbr

east

milk

insm

alla

mou

nts

(Pro

duct

info

rmat

ion

Bic

illin

,200

1;pr

oduc

tin

form

atio

nPe

nici

llin

V,1

997)

.15

Con

side

red

“usu

ally

com

patib

lew

ithbr

east

feed

ing.

”9†

Inw

omen

with

seru

mco

ncen

trat

ions

ofpe

nici

llin

rang

ing

from

6to

120

�g/

dL,c

orre

spon

ding

brea

stm

ilkco

ncen

trat

ions

wer

e1.

2–3.

6�

g/dL

,an

dth

eam

ount

ofth

em

ater

nald

ose

appe

arin

gin

brea

stm

ilkpe

rda

yw

ases

timat

edat

0.03

%.15

Shor

ter

dosi

ngin

terv

alan

d/or

incr

ease

ddo

seha

vebe

ensu

gges

ted

duri

ngpr

egna

ncy

toat

tain

sim

ilar

plas

ma

conc

entr

atio

nsas

for

nonp

regn

antw

omen

.6,11

Peni

cilli

nsar

epr

imar

ilyre

nally

excr

eted

via

tubu

lar

secr

etio

nan

dgl

omer

ular

filtr

atio

n.V

olum

eof

dist

ribu

tion

and

rena

lcl

eara

nce

are

incr

ease

ddu

ring

the

2nd

and

3rd

trim

este

rs.6,

11

Peni

cilli

nV

KG

ram

-pos

itive

aero

bes

incl

udin

gm

ost

stre

ptoc

occi

/en

tero

cocc

i,gr

am-

posi

tive

anae

robe

s,gr

amne

gativ

es

Cro

sses

the

hum

anpl

acen

tare

adily

.5,7,

10,3

3,34

,35

Peni

cilli

nsar

etr

ansf

erre

dto

the

fetu

san

dam

niot

icflu

idre

achi

ngth

erap

eutic

leve

ls.5

Exc

rete

din

hum

anbr

east

milk

insm

alla

mou

nts

(Pro

duct

info

rmat

ion

Peni

cilli

nV

,199

7).15

,36

Con

side

red

“usu

ally

com

patib

lew

ithbr

east

feed

ing.

”9†

In18

wom

en,p

enic

illin

Vm

ilkco

ncen

trat

ion

depe

nded

onpr

esen

ceof

mas

titis

,with

peak

leve

ls2.

6–5.

4ho

urs

afte

ra

sing

lePO

1,32

0-m

gdo

se.35

Peak

conc

entr

atio

nw

as30

–72

�g/

dLw

ithm

ean

conc

entr

atio

n26

-37

�g/

dL.A

UC

over

8ho

urs

afte

rdo

sing

was

2.1–

3.0

mg-

h/L

.35

Est

imat

eddo

seof

peni

cilli

nV

inge

sted

per

day

bybr

east

fed

infa

nts

is40

–60

�g/

kg,o

r0.

09–

0.14

%of

mat

erna

ldos

epe

rkg

body

wei

ght.35

Shor

ter

dosi

ngin

terv

alan

d/or

incr

ease

ddo

seha

vebe

ensu

gges

ted

duri

ngpr

egna

ncy

toat

tain

sim

ilar

plas

ma

conc

entr

atio

nsas

for

nonp

regn

ant

wom

en.6,

11

Peni

cilli

nV

isex

cret

edre

nally

,pr

imar

ilyvi

atu

bula

rse

cret

ion.

Vol

ume

ofdi

stri

butio

nan

dre

nal

clea

ranc

ear

ein

crea

sed

duri

ngth

e2n

dan

d3r

dtr

imes

ters

.6,11

(con

tinue

d)

VOL. 107, NO. 5, MAY 2006 Nahum et al Antibiotic Use in Pregnancy 1125

Tabl

e2.

Cur

rent

Info

rmat

ion

for

Elev

enB

road

-Sp

ectr

umA

ntib

ioti

csTh

atM

ayB

eU

sed

inPr

egna

ntan

dLa

ctat

ing

Wo

men

(co

ntin

ued

)

Ant

ibio

tic

Mic

rob

iolo

gic

Spec

trum

of

Act

ivit

y*Pl

acen

tal

Tran

smis

sio

nTr

ansm

issi

on

Into

Bre

ast

Milk

Poss

ible

Preg

nanc

yD

osa

ge/

Sche

dul

eA

dju

stm

ents

,M

etab

olis

m,

Excr

etio

n,an

dR

eco

mm

end

atio

nsfo

rM

oni

tori

ng

Rifa

mpi

nM

ycob

acte

ria,

Nei

sser

iam

enin

gitid

is,S

aure

us,

Hae

mop

hilu

sin

fluen

zae,

Legi

onel

lapn

eum

ophi

la,

Chl

amyd

ia

Cro

sses

the

hum

anpl

acen

ta(P

rodu

ctin

form

atio

nR

ifam

pin,

1971

).37–3

9

Um

bilic

alco

rdco

ncen

trat

ions

betw

een

12%

and

33%

ofm

ater

nalb

lood

leve

ls,w

ithpe

akle

vels

occu

rrin

gco

ncur

rent

lyaf

ter

drug

adm

inis

trat

ion.

37–3

9

Exc

rete

din

hum

anbr

east

milk

(Pro

duct

info

rmat

ion

Rifa

mpi

n,19

71).15

,40,

41

Con

side

red

“usu

ally

com

patib

lew

ithbr

east

feed

ing.

”9†

Afte

ra

sing

leor

aldo

seof

600

mg,

anu

rsin

gin

fant

wou

ldin

gest

appr

oxim

atel

y0.

05%

ofth

em

ater

nald

ose

per

day,

orap

prox

imat

ely

0.3

mg/

day.

15,4

0,41

Unk

now

nw

heth

erdo

sing

adju

stm

ents

duri

ngpr

egna

ncy

are

nece

ssar

y.Ph

arm

acok

inet

ics

duri

ngpr

egna

ncy

has

not

been

spec

ifica

llyst

udie

d.H

epat

ical

lyde

acet

ylat

edto

activ

em

etab

olite

.Par

ent

com

poun

dan

dm

etab

olite

sex

cret

edvi

abi

liary

elim

inat

ion

(60%

).E

nter

ohep

atic

re-c

ircu

latio

n;pl

asm

ale

vels

elev

ated

inhe

patic

dise

ase.

Up

to30

%ex

cret

edin

urin

e;re

nal

clea

ranc

eis

12%

ofG

FR.38

Van

com

ycin

Gra

mpo

sitiv

es,S

aure

us,

Stap

hylo

cocc

usep

ider

mid

is,st

rept

ococ

ci,

ente

roco

cci,

Clo

strid

ium

,Cor

yne-

bact

eriu

m

Cro

sses

the

hum

anpl

acen

ta(P

rodu

ctin

form

atio

nV

anco

myc

in,1

964)

.42,4

3

App

ears

inum

bilic

alco

rdbl

ood

afte

rIV

mat

erna

ltr

eatm

ent

(Pro

duct

info

rmat

ion

Van

com

ycin

,19

64).42

,43

Am

niot

icflu

idan

dum

bilic

alco

rdbl

ood

conc

entr

atio

nsdu

ring

the

earl

y3r

dtr

imes

ter

com

para

ble

tom

ater

nalb

lood

leve

ls(fe

tal-m

ater

nal

seru

mco

ncen

trat

ion

ratio

of0.

76).43

Exc

rete

din

hum

anbr

east

milk

whe

nad

min

iste

red

IV(P

rodu

ctin

form

atio

nV

anco

myc

in,1

964)

.42

Whe

nad

min

iste

red

oral

ly,v

anco

myc

inis

poor

lyab

sorb

edfr

omth

eG

Itr

act

(Pro

duct

info

rmat

ion

Van

com

ycin

,196

4).I

tis

,the

refo

re,

not

likel

yto

caus

ead

vers

eef

fect

sin

nurs

ing

infa

nts.

The

rear

eno

stud

ies

toin

dica

teth

atva

ncom

ycin

dosi

ngsh

ould

bem

odifi

eddu

ring

preg

nanc

y.V

olum

eof

dist

ribu

tion

and

plas

ma

clea

ranc

ebo

thin

crea

sed,

but

half-

life

sim

ilar

toth

atfo

rno

npre

gnan

tw

omen

(4.5

5ve

rsus

4–6

hour

s)in

aw

oman

adm

inis

tere

dIV

vanc

omyc

intw

ice

daily

from

26–2

8w

eeks

ofpr

egna

ncy.

43

CB

C,c

ompl

ete

bloo

dco

unt;

AF,

amni

otic

fluid

;M

S,m

ater

nals

erum

;G

I,ga

stro

inte

stin

al;

AU

C,a

rea

unde

rth

ecu

rve;

GFR

,glo

mer

ular

filtr

atio

nra

te.

*L

iste

din

the

prod

uct

labe

lan

dth

ecl

inic

alph

arm

acol

ogy

mon

ogra

phas

activ

eag

ains

tm

ost

stra

ins;

bact

eria

lre

sist

ance

occu

rsco

mm

only

inso

me

spec

ies

ofot

herw

ise

susc

eptib

leba

cter

iadu

eto

beta

-lact

amas

epr

oduc

tion.

†B

ased

onas

sess

men

tby

the

Am

eric

anA

cade

my

ofPe

diat

rics

.

1126 Nahum et al Antibiotic Use in Pregnancy OBSTETRICS & GYNECOLOGY

Tabl

e3.

Tera

toge

nic

and

Toxi

cPo

tent

ial

of

Elev

enB

road

-Sp

ectr

umA

ntib

ioti

csB

ased

on

Ava

ilab

leH

uman

and

Ani

mal

Dat

a

Ant

ibio

tic

Hum

anD

ata:

Tera

toge

nic

and

Toxi

cEf

fect

sA

nim

alD

ata:

Tera

toge

nic

and

Toxi

cFe

tal

Effe

cts

Mag

nitu

de

of

Hum

anTe

rato

geni

cFe

tal

Ris

k(B

ased

on

TER

ISA

sses

smen

t)44

FDA

Preg

nanc

yC

ateg

ory

*

Am

oxic

illin

OR

for

maj

orco

ngen

itala

nom

alie

s�

1.4

(95%

CI

0.9–

2.0)

for

wom

enus

ing

amox

icill

in�

clav

ulan

icac

iddu

ring

preg

nanc

yin

aca

se-c

ontr

olst

udy

of6,

935

mal

form

edin

fant

s(n

oin

crea

sed

risk

).45

OR

(adj

uste

d)fo

rco

ngen

itala

nom

alie

s�

1.16

(95%

CI

0.54

–2.

50)

ina

Dan

ish

stud

y(1

991–

2000

)of

401

prim

ipar

ous

wom

enw

hofil

led

pres

crip

tions

for

amox

icill

indu

ring

preg

nanc

y(r

ate

�4.

0%)

com

pare

dw

ith10

,237

cont

rols

who

did

not

rede

eman

ypr

escr

iptio

ndr

ug(r

ate

�4.

1%).46

No

incr

ease

dra

teof

cong

enita

lmal

form

atio

nsam

ong

147

wom

enw

hore

ceiv

edpr

escr

iptio

nsfo

ram

oxic

illin

duri

ngth

e1s

ttr

imes

ter.

46

No

incr

ease

dra

teof

cong

enita

lano

mal

ies

amon

g28

4in

fant

sw

hose

mot

hers

wer

ead

min

iste

red

amox

icill

inor

ampi

cilli

ndu

ring

the

1st

trim

este

r,or

in1,

060

infa

nts

who

sem

othe

rsw

ere

trea

ted

atan

ytim

edu

ring

preg

nanc

y.47

No

sign

ifica

ntly

incr

ease

dra

teof

maj

oror

min

oran

omal

ies

inth

ech

ildre

nof

14w

omen

trea

ted

with

amox

icill

inan

dpr

oben

ecid

duri

ngth

efir

st14

wee

ksof

gest

atio

nor

amon

g57

wom

entr

eate

daf

ter

the

14th

wee

kin

aco

ntro

lled

clin

ical

tria

lon

the

trea

tmen

tof

gono

rrhe

adu

ring

preg

nanc

y.48

No

adve

rse

effe

cts

inof

fspr

ing

expo

sed

toam

oxic

illin

duri

ngth

e2n

dan

d3r

dtr

imes

ters

in3

cont

rolle

dcl

inic

altr

ials

ofan

tibio

tictr

eatm

ent

for

prem

atur

epr

eter

mru

ptur

eof

mem

bran

es.49

–51

An

asso

ciat

ion

ofne

crot

izin

gen

tero

colit

isin

new

born

san

dm

ater

nala

mox

icill

inan

dcl

avul

anic

acid

trea

tmen

tdu

ring

the

3rd

trim

este

rw

asob

serv

edin

ara

ndom

ized

cont

rolle

dtr

iali

nclu

ding

4,82

6pr

egna

ntpa

tient

s.52

,53

No

incr

ease

dco

ngen

ital

mal

form

atio

nsin

mic

etr

eate

dw

ith3–

7tim

esth

em

axim

umhu

man

ther

apeu

ticdo

seof

amox

icill

in.54

No

adve

rse

repr

oduc

tive

effe

cts

inra

tsgi

ven

amox

icill

in-

clav

ulan

icac

idat

dose

sof

400

and

1,20

0m

g/da

ypr

ior

tofe

rtili

zatio

nan

ddu

ring

the

first

7da

ysof

gest

atio

n(P

rodu

ctin

form

atio

nA

mox

il,20

01).55

No

adve

rse

feta

leffe

cts

inpi

gsgi

ven

amox

icill

inw

ithcl

avul

anic

acid

atdo

ses

of60

0m

g/kg

onda

ys12

–42.

56

Incr

ease

dfr

eque

ncy

ofem

bryo

nic

deat

hin

mic

etr

eate

dw

itham

oxic

illin

at6–

7tim

esth

em

axim

umth

erap

eutic

hum

ando

se.54

Incr

ease

dri

skof

tera

toge

nici

tyis

“unl

ikel

y,”

base

don

“fai

r”da

ta.

B

Chl

oram

phen

icol

OR

for

maj

orco

ngen

itala

nom

alie

s�

1.7

(95%

CI

1.2–

2.6)

for

oral

adm

inis

trat

ion

atan

ytim

edu

ring

preg

nanc

yin

aca

se-

cont

rols

tudy

of22

,865

mal

form

edin

fant

s(r

isk

mar

gina

llyin

crea

sed)

.57

RR

for

cong

enita

lmal

form

atio

ns�

1.19

(95%

CI

0.52

–2.3

1)in

348

offs

prin

gbo

rnto

wom

enw

hoto

okch

lora

mph

enic

olat

any

time

duri

ngpr

egna

ncy

(no

stat

istic

ally

incr

ease

dri

sk).58

Pote

ntia

lfor

both

dose

-rel

ated

and

idio

sync

ratic

bone

mar

row

toxi

city

.Cau

tion

shou

ldbe

used

near

term

,dur

ing

labo

r,an

dw

hile

brea

stfe

edin

gdu

eto

the

poss

ibili

tyof

indu

cing

“gra

y-ba

by”

synd

rom

e.59

No

incr

ease

dco

ngen

ital

anom

alie

sin

mon

keys

.60

No

tera

toge

nici

tyin

mic

eor

rabb

itsat

10–4

0tim

esth

ere

com

men

ded

hum

ando

se.61

No

tera

toge

nici

tyin

rats

at2–

4tim

esth

eus

ualh

uman

dose

,62

but

vari

ous

feta

lano

mal

ies

at10

–40

times

the

hum

ando

se.61

,63

Incr

ease

dfe

tald

eath

and

decr

ease

dfe

talw

eigh

tin

mic

e,ra

ts,a

ndra

bbits

.61–6

3

Incr

ease

dri

skof

tera

toge

nici

tyis

“unl

ikel

y,”

base

don

“fai

r”da

ta.

“The

rape

utic

dose

sof

chlo

ram

phen

icol

are

unlik

ely

topo

sea

subs

tant

ial

tera

toge

nic

risk

.”

C

(con

tinue

d)

VOL. 107, NO. 5, MAY 2006 Nahum et al Antibiotic Use in Pregnancy 1127

Tabl

e3.

Tera

toge

nic

and

Toxi

cPo

tent

ial

of

Elev

enB

road

-Sp

ectr

umA

ntib

ioti

csB

ased

on

Ava

ilab

leH

uman

and

Ani

mal

Dat

a(c

ont

inue

d)

Ant

ibio

tic

Hum

anD

ata:

Tera

toge

nic

and

Toxi

cEf

fect

sA

nim

alD

ata:

Tera

toge

nic

and

Toxi

cFe

tal

Effe

cts

Mag

nitu

de

of

Hum

anTe

rato

geni

cFe

tal

Ris

k(B

ased

on

TER

ISA

sses

smen

t)44

FDA

Preg

nanc

yC

ateg

ory

*

Cip

roflo

xaci

nC

onge

nita

lmal

form

atio

nra

te�

4.0%

and

spon

tane

ous

abor

tion

rate

�10

.7%

amon

gliv

ebor

nsto

56w

omen

who

cont

inue

dth

eir

preg

nanc

ies

afte

rex

posu

reto

cipr

oflo

xaci

n(E

NT

ISre

gist

ry,1

986–

1994

).R

ates

ofsp

onta

neou

sab

ortio

n/fe

tald

eath

,pos

t-nat

aldi

sord

ers,

prem

atur

ityan

din

tra-

uter

ine

grow

thre

tard

atio

ndi

dno

tex

ceed

back

grou

ndra

tes.

64

Ina

pros

pect

ive

regi

stry

of11

6pr

egna

ncie

sex

pose

dto

cipr

oflo

xaci

n,91

resu

lted

inliv

ebi

rths

and

69%

ofth

ese

wer

eex

pose

ddu

ring

the

1st

trim

este

r.Si

xliv

ebor

nsw

ere

mal

form

ed(c

onge

nita

lmal

form

atio

nra

te�

6.6%

).T

here

was

nopa

ttern

ofm

inor

orm

ajor

mal

form

atio

ns.64

OR

for

maj

orco

ngen

itala

nom

alie

s�

0.85

(95%

CI

0.21

–3.

49)

ina

cont

rolle

d,pr

ospe

ctiv

e,ob

serv

atio

nals

tudy

of20

0hu

man

preg

nanc

ies

expo

sed

toflu

oroq

uino

lone

sdu

ring

the

1st

trim

este

r(2

.2%

rate

vers

us2.

6%in

cont

rols

)[5

3%ci

prof

loxa

cin

expo

sure

s,w

ith68

%du

ring

the

1st

trim

este

r](n

oin

crea

sed

risk

).65N

ocl

inic

ally

sign

ifica

ntm

uscu

losk

elet

alor

deve

lopm

enta

ldys

func

tions

inof

fspr

ing.

65

No

cong

enita

lmal

form

atio

nsan

dno

incr

ease

inm

uscu

losk

elet

alpr

oble

ms

inof

fspr

ing

of28

preg

nant

wom

enex

pose

dto

cipr

oflo

xaci

ndu

ring

the

1st

trim

este

r.65

Perm

anen

tqu

inol

one-

indu

ced

cart

ilage

orbo

neda

mag

eha

sno

tbe

endo

cum

ente

din

hum

ans.

66,6

7Se

ven

wom

enex

pose

dto

cipr

oflo

xaci

ndu

ring

2nd

or3r

dtr

imes

ter

deliv

ered

heal

thy,

norm

alba

bies

.Mot

or,a

dapt

ive,

soci

al,

and

lang

uage

mile

ston

esw

ere

cons

iste

ntw

ithag

e,an

dth

ere

was

noev

iden

ceof

cart

ilage

dam

age

onre

gula

rcl

inic

alas

sess

men

tsup

to5

year

sof

age.

68

No

dete

ctab

lead

vers

eef

fect

son

embr

yoni

cor

feta

lde

velo

pmen

tin

mon

keys

.69

No

evid

ence

ofte

rato

geni

city

inth

eof

fspr

ing

ofm

ice,

rats

,and

rabb

its.70

Incr

ease

dri

skof

tera

toge

nici

tyis

“unl

ikel

y,”

base

don

“fai

r”da

ta.

“The

rape

utic

dose

sof

cipr

oflo

xaci

ndu

ring

preg

nanc

yar

eun

likel

yto

pose

asu

bsta

ntia

lter

atog

enic

risk

,but

the

data

are

insu

ffici

ent

tost

ate

that

ther

eis

no[in

crea

sed]

risk

”.

C

Clin

dam

ycin

Maj

orco

ngen

itala

nom

alie

sin

31of

647

infa

nts

(4.8

%)

who

sem

othe

rsw

ere

give

npr

escr

iptio

nsfo

rcl

inda

myc

indu

ring

the

1st

trim

este

rof

preg

nanc

y;ex

pect

edra

te4.

3%.71

No

incr

ease

dra

teof

cong

enita

lmal

form

atio

nsin

104

wom

entr

eate

dw

ithcl

inda

myc

indu

ring

the

2nd

or3r

dtr

imes

ter

ofpr

egna

ncy

for

the

prev

entio

nof

pret

erm

deliv

ery.

72

No

incr

ease

dra

teof

cong

enita

lano

mal

ies

in65

infa

nts

born

tow

omen

who

rece

ived

clin

dam

ycin

and

quin

ine

duri

ngth

e2n

dor

3rd

trim

este

rof

preg

nanc

yfo

rth

etr

eatm

ent

ofm

alar

ia.73

No

incr

ease

dco

ngen

ital

mal

form

atio

nsin

mic

ean

dra

tsgi

ven

1–12

times

the

ther

apeu

tichu

man

dose

.77,7

8

Incr

ease

dri

skof

tera

toge

nici

tyis

“und

eter

min

ed”

base

don

“lim

ited”

data

.“A

lthou

gha

smal

l[in

crea

sed]

risk

cann

otbe

excl

uded

,ahi

ghri

skof

cong

enita

lano

mal

ies

inth

ech

ildre

nof

wom

entr

eate

dw

ithcl

inda

myc

indu

ring

preg

nanc

yis

unlik

ely”

.

B

(con

tinue

d)

1128 Nahum et al Antibiotic Use in Pregnancy OBSTETRICS & GYNECOLOGY

Tabl

e3.

Tera

toge

nic

and

Toxi

cPo

tent

ial

of

Elev

enB

road

-Sp

ectr

umA

ntib

ioti

csB

ased

on

Ava

ilab

leH

uman

and

Ani

mal

Dat

a(c

ont

inue

d)

Ant

ibio

tic

Hum

anD

ata:

Tera

toge

nic

and

Toxi

cEf

fect

sA

nim

alD

ata:

Tera

toge

nic

and

Toxi

cFe

tal

Effe

cts

Mag

nitu

de

of

Hum

anTe

rato

geni

cFe

tal

Ris

k(B

ased

on

TER

ISA

sses

smen

t)44

FDA

Preg

nanc

yC

ateg

ory

*

Clin

dam

ycin

(con

tinue

d)N

oco

ngen

italm

alfo

rmat

ions

amon

g16

child

ren

ofw

omen

trea

ted

with

clin

dam

ycin

duri

ngth

e1s

ttr

imes

ter

ofpr

egna

ncy

for

atte

mpt

edpr

even

tion

ofre

curr

ent

mis

carr

iage

.74

Can

bea

caus

ativ

efa

ctor

inth

ede

velo

pmen

tof

pseu

dom

embr

anou

sco

litis

due

toov

ergr

owth

ofC

lostr

idiu

mdi

ffici

le.O

ccur

sin

freq

uent

lyan

dno

mor

eco

mm

onam

ong

preg

nant

wom

enus

ing

clin

dam

ycin

than

nonp

regn

ant.75

Has

occu

rred

with

use

ofne

arly

alla

ntib

acte

rial

agen

ts,

incl

udin

gcl

inda

myc

in(P

rodu

ctin

form

atio

nC

linda

myc

in,

1970

).A

nin

fant

deve

lope

dbl

oody

stoo

lsaf

ter

expo

sure

tocl

inda

myc

inan

dge

ntam

icin

inbr

east

milk

;no

bloo

dan

dbr

east

milk

sam

ples

wer

eob

tain

edan

da

caus

ativ

ere

latio

nshi

pw

asno

tes

tabl

ishe

d.76

Dox

ycyc

line

OR

for

maj

orco

ngen

itala

nom

alie

s�

1.6

(95%

CI

1.1–

2.3)

for

wom

enre

ceiv

ing

doxy

cycl

ine

atan

ytim

edu

ring

preg

nanc

yin

aca

se-c

ontr

olst

udy

of18

,515

infa

nts

with

cong

enita

labn

orm

aliti

es(r

isk

mar

gina

llyin

crea

sed)

.79

OR

of1.

6w

asno

tsi

gnifi

cant

lyin

crea

sed

(95%

CI

0.8–

3.6)

for

ase

para

tely

anal

yzed

subg

roup

expo

sed

duri

ngor

gano

gene

sis

(2–3

mon

ths

ofpr

egna

ncy)

.79

No

asso

ciat

ion

ofco

ngen

italm

alfo

rmat

ions

with

doxy

cycl

ine

expo

sure

for

any

of6

anom

alie

s(c

ardi

ovas

cula

rde

fect

s,or

alcl

efts

,spi

nabi

fida,

poly

dact

yly,

limb

redu

ctio

nde

fect

s,an

dhy

posp

adia

s)am

ong

1,79

5do

xycy

clin

e-ex

pose

dpr

egna

ncie

sin

229,

101

com

plet

edpr

egna

ncie

sin

asu

rvei

llanc

est

udy

ofM

edic

aid

reci

pien

ts.71

All

mot

hers

repo

rted

that

expo

sed

infa

nts

wer

eno

rmal

at1

year

ofag

ein

apr

ospe

ctiv

est

udy

of81

preg

nanc

ies

trea

ted

with

doxy

cycl

ine

for

10da

ysdu

ring

the

earl

y1s

ttr

imes

ter.

80

Tet

racy

clin

ecl

ass

antib

iotic

sm

ayin

duce

hepa

ticne

cros

isin

som

epr

egna

ntw

omen

.81–8

3

Som

ete

trac

yclin

esca

nca

use

cosm

etic

stai

ning

ofpr

imar

yde

ntiti

onfo

rex

posu

res

duri

ngth

e2n

dor

3rd

trim

este

r,84

,85

and

ther

eis

som

eco

ncer

nab

out

poss

ible

enam

elhy

popl

asia

and

reve

rsib

lede

pres

sion

offe

talb

one

grow

th.86

No

stai

ning

from

doxy

cycl

ine

has

been

docu

men

ted

inhu

man

s.

No

incr

ease

inco

ngen

ital

anom

alie

sin

mic

etr

eate

dw

ith2–

6tim

esth

em

axim

umhu

man

dose

.87

Incr

ease

dsk

elet

alan

omal

ies

and

decr

ease

dfe

talw

eigh

tin

mic

eat

17tim

esth

em

axim

umhu

man

dose

.87

No

tera

toge

nici

tyin

rabb

itsgi

ven

2–17

times

the

max

imum

hum

ando

se,b

utde

crea

sed

feta

lwei

ght

and

incr

ease

dfe

tald

eath

athi

gher

dose

s.87

,88

No

tera

toge

nici

tyin

rats

orm

onke

ysat

mor

eth

an10

0tim

esth

ehu

man

dose

.89

Del

ayed

long

bone

skel

etal

diffe

rent

iatio

nin

albi

nora

tsgi

ven

8m

g/kg

ofdo

xycy

clin

ein

trap

erito

neal

lyfr

omge

stat

iona

lday

8to

19.90

Del

ayed

appe

aran

ceof

prim

ary

ossi

ficat

ion

cent

ers

inth

ehu

mer

us,u

lna,

radi

us,

fem

ur,t

ibia

,and

fibul

aco

mpa

red

with

cont

rols

(P�

.001

).90

Incr

ease

dri

skof

tera

toge

nici

tyis

“unl

ikel

y,”

base

don

“fai

r”da

ta.

“The

rape

utic

dose

sof

doxy

cycl

ine

are

unlik

ely

topo

sea

subs

tant

ialr

isk

offe

talm

alfo

rmat

ions

,but

the

data

are

insu

ffici

ent

tost

ate

that

ther

eis

no[in

crea

sed]

risk

.”In

crea

sed

risk

ofde

ntal

stai

ning

is“u

ndet

erm

ined

”ba

sed

on“v

ery

limite

d”da

ta.

D

(con

tinue

d)

VOL. 107, NO. 5, MAY 2006 Nahum et al Antibiotic Use in Pregnancy 1129

Tabl

e3.

Tera

toge

nic

and

Toxi

cPo

tent

ial

of

Elev

enB

road

-Sp

ectr

umA

ntib

ioti

csB

ased

on

Ava

ilab

leH

uman

and

Ani

mal

Dat

a(c

ont

inue

d)

Ant

ibio

tic

Hum

anD

ata:

Tera

toge

nic

and

Toxi

cEf

fect

sA

nim

alD

ata:

Tera

toge

nic

and

Toxi

cFe

tal

Effe

cts

Mag

nitu

de

of

Hum

anTe

rato

geni

cFe

tal

Ris

k(B

ased

on

TER

ISA

sses

smen

t)44

FDA

Preg

nanc

yC

ateg

ory

*

Gen

tam

icin

OR

for

maj

orco

ngen

itala

nom

alie

s�

1.7

(95%

CI

0.9–

3.2)

,in

aca

se-c

ontr

olst

udy

of22

,865

infa

nts

with

cong

enita

lan

omal

ies

(no

incr

ease

dri

sk);

incl

uded

19cr

itica

lex

posu

res,

with

the

maj

ority

occu

rrin

gdu

ring

the

2nd

or3r

dm

onth

ofpr

egna

ncy.

91

Ara

ndom

ized

tria

lof

3pa

rent

eral

antib

iotic

regi

men

ssh

owed

noco

ngen

itala

bnor

mal

ities

amon

g57

infa

nts

who

sem

othe

rsw

ere

trea

ted

with

gent

amic

indu

ring

the

1st

or2n

dtr

imes

ters

.92

The

freq

uenc

yof

new

born

hear

ing

scre

enin

gfa

ilure

sw

asno

tdi

ffere

ntbe

twee

n46

infa

nts

who

sem

othe

rsw

ere

trea

ted

with

gent

amic

indu

ring

preg

nanc

yan

d92

unex

pose

dco

ntro

linf

ants

.93

Ren

alcy

stic

dysp

lasi

aw

asre

port

edin

ach

ildw

hose

mot

her

was

give

nge

ntam

icin

duri

ngth

e7t

hw

eek

ofpr

egna

ncy.

94

The

reis

nopr

oof

ofa

caus

alre

latio

nshi

pbe

twee

nth

ege

ntam

icin

trea

tmen

tan

dth

ene

phro

toxi

city

,but

itca

nnot

beex

clud

ed.94

No

otot

oxic

ityor

neph

roto

xici

tyha

sbe

endo

cum

ente

din

hum

anfe

tuse

s.44

Mic

egi

ven

1–12

times

the

max

imum

hum

ando

seha

da

slig

htst

atis

tical

lyno

nsig

nific

ant

incr

ease

inth

era

teof

cong

enita

lano

mal

ies

atlo

wer

dose

s,bu

tno

thi

gher

ones

.95Fe

tald

eath

sw

ere

incr

ease

d.95

Inm

ice

trea

ted

with

11–1

8tim

esth

em

axim

umhu

man

dose

,do

se-d

epen

dent

ultr

astr

uctu

ral

vest

ibul

arsy

stem

dam

age

was

dem

onst

rate

din

offs

prin

g.96

Inra

tstr

eate

dsy

stem

ical

lyw

ithda

ilydo

ses

upto

500

times

the

max

imum

hum

anop

htha

lmic

dose

,gen

tam

icin

depr

esse

dm

edia

ngl

omer

ular

coun

tsan

dki

dney

and

body

wei

ghts

inne

wbo

rns

(Pro

duct

info

rmat

ion

Gen

tam

icin

,19

66).

Rat

sgi

ven

9–25

times

the

max

imum

hum

ando

seha

dne

phro

toxi

city

inof

fspr

ing

ofty

pety

pica

llyex

pect

edfr

omam

inog

lyco

side

expo

sure

.97

Incr

ease

dri

skof

tera

toge

nici

tyis

“und

eter

min

ed”

base

don

“lim

ited”

data

.“A

smal

l[in

crea

sed]

risk

cann

otbe

excl

uded

,but

ther

eis

noin

dica

tion

that

the

risk

ofm

alfo

rmat

ions

inch

ildre

nof

wom

entr

eate

dw

ithge

ntam

icin

duri

ngpr

egna

ncy

islik

ely

tobe

grea

t.”

C

Lev

oflo

xaci

nN

ow

ell-c

ontr

olle

dst

udie

sof

the

safe

tyan

def

ficac

yof

levo

floxa

cin

inpr

egna

ntor

lact

atin

gw

omen

have

been

repo

rted

.

No

tera

toge

nici

tyin

rats

ator

aldo

ses

upto

810

mg/

kgpe

rda

y(9

.4tim

esth

em

axim

umhu

man

dose

base

don

BSA

)or

IVdo

ses

upto

160

mg/

kgpe

rda

y(1

.9tim

esth

em

axim

umhu

man

dose

)(P

rodu

ctin

form

atio

nL

evaq

uin,

1996

).

The

rear

eno

wel

l-con

trol

led

stud

ies

ofth

esa

fety

and

effic

acy

ofle

voflo

xaci

nin

preg

nant

orla

ctat

ing

wom

en.

Com

preh

ensi

vere

view

sof

publ

ishe

dda

taco

ncer

ning

norf

loxa

cin

and

cipr

oflo

xaci

n(2

rela

ted

fluor

oqui

nolo

nean

tibio

tics)

conc

lude

that

anin

crea

sed

risk

ofte

rato

geni

city

is“u

nlik

ely”

base

don

“fai

r”da

ta.

C

(con

tinue

d)

1130 Nahum et al Antibiotic Use in Pregnancy OBSTETRICS & GYNECOLOGY

Tabl

e3.

Tera

toge

nic

and

Toxi

cPo

tent

ial

of

Elev

enB

road

-Sp

ectr

umA

ntib

ioti

csB

ased

on

Ava

ilab

leH

uman

and

Ani

mal

Dat

a(c

ont

inue

d)

Ant

ibio

tic

Hum

anD

ata:

Tera

toge

nic

and

Toxi

cEf

fect

sA

nim

alD

ata:

Tera

toge

nic

and

Toxi

cFe

tal

Effe

cts

Mag

nitu

de

of

Hum

anTe

rato

geni

cFe

tal

Ris

k(B

ased

on

TER

ISA

sses

smen

t)44

FDA

Preg

nanc

yC

ateg

ory

*

Lev

oflo

xaci

n(c

ontin

ued)

No

tera

toge

nici

tyor

adve

rse

effe

cts

onfe

rtili

tyin

rats

ator

aldo

ses

upto

360

mg/

kgpe

rda

y.91

Dec

reas

edfe

tal

body

wei

ght

and

incr

ease

dfe

talm

orta

lity

inra

tsgi

ven

810

mg/

kgpe

rda

y,w

ithre

tard

atio

nof

feta

lske

leta

los

sific

atio

n/sk

elet

alva

riat

ions

(Pro

duct

info

rmat

ion

Lev

aqui

n,19

96).98

No

tera

toge

nici

tyin

rabb

itsgi

ven

upto

50m

g/kg

per

day

oral

ly(1

.1tim

esth

em

axim

umre

com

men

ded

hum

ando

seba

sed

onB

SA),

orIV

atdo

ses

upto

25m

g/kg

per

day

(0.5

times

the

high

est

reco

mm

ende

dhu

man

dose

)(P

rodu

ctin

form

atio

nL

evaq

uin,

1996

).98

Peni

cilli

nG

OR

for

maj

orco

ngen

itala

nom

alie

s�

1.3

(95%

CI

1.1–

1.5)

for

wom

enw

hous

edpe

nici

llin

Gdu

ring

preg

nanc

yin

aca

se-c

ontr

olst

udy

(198

0-19

96)

of22

,865

mal

form

edin

fant

s(m

argi

nally

incr

ease

dri

sksu

gges

ted

attr

ibut

able

tore

call

bias

byth

eau

thor

s).99

RR

for

cong

enita

lmal

form

atio

ns�

0.92

(95%

CI

0.78

–1.1

0)am

ong

7,17

1in

fant

sw

hose

mot

hers

wer

etr

eate

dw

itha

peni

cilli

nde

riva

tive

atan

ytim

edu

ring

preg

nanc

y(n

oin

crea

sed

risk

).58

The

freq

uenc

yof

1st-t

rim

este

rpe

nici

llin

use

was

nogr

eate

rth

anex

pect

edin

apr

ospe

ctiv

est

udy

of19

4in

fant

sw

ithm

ajor

mal

form

atio

nsbo

rnin

Swed

en(1

963–

1965

).100

OR

for

neur

altu

bede

fect

s�

0.90

(95%

CI

0.37

–2.1

7).R

ate

of1s

t-tri

mes

ter

peni

cilli

nus

ew

asno

grea

ter

than

expe

cted

ina

case

-con

trol

stud

yof

538

infa

nts

with

neur

altu

bede

fect

san

d53

9co

ntro

lsin

Cal

iforn

iafr

om19

89to

1991

(no

incr

ease

dri

sk).10

1

No

adve

rse

effe

cts

note

din

offs

prin

gde

spite

wid

espr

ead

use

ofpe

nici

llins

duri

ngpr

egna

ncy.

10,4

4,58

,99,

102

No

tera

toge

nici

tyin

mic

ead

min

iste

red

upto

500

units

/gon

gest

atio

nda

y14

.103

No

tera

toge

nici

tyor

incr

ease

dab

ortio

nsin

rabb

itsm

aint

aine

don

100

mg/

kgpe

rda

ydu

ring

preg

nanc

y.10

4

No

tera

toge

nici

tyor

impa

ired

fert

ility

inm

ice,

rats

and

rabb

its(P

rodu

ctin

form

atio

nB

icill

in,2

001)

.

Incr

ease

dri

skof

tera

toge

nici

tyis

“non

e”ba

sed

on“g

ood”

data

.B

(con

tinue

d)

VOL. 107, NO. 5, MAY 2006 Nahum et al Antibiotic Use in Pregnancy 1131

Tabl

e3.

Tera

toge

nic

and

Toxi

cPo

tent

ial

of

Elev

enB

road

-Sp

ectr

umA

ntib

ioti

csB

ased

on

Ava

ilab

leH

uman

and

Ani

mal

Dat

a(c

ont

inue

d)

Ant

ibio

tic

Hum

anD

ata:

Tera

toge

nic

and

Toxi

cEf

fect

sA

nim

alD

ata:

Tera

toge

nic

and

Toxi

cFe

tal

Effe

cts

Mag

nitu

de

of

Hum

anTe

rato

geni

cFe

tal

Ris

k(B

ased

on

TER

ISA

sses

smen

t)44

FDA

Preg

nanc

yC

ateg

ory

*

Peni

cilli

nV

KO

Rfo

rco

ngen

itala

nom

alie

s�

1.25

(95%

CI

0.84

–1.8

6)(n

otin

crea

sed)

amon

g65

4us

ers

ofpe

nici

llin

VK

with

orw

ithou

tot

her

drug

use

duri

ngth

e1s

ttr

imes

ter

(199

1–19

98).

The

rate

ofco

ngen

itala

nom

alie

s(4

.6%

)w

asno

grea

ter

than

for

9,26

3co

ntro

lsw

hodi

dno

tre

deem

any

pres

crip

tion

drug

duri

ngpr

egna

ncy

(3.6

%).10

5N

ine

card

iova

scul

arab

norm

aliti

esoc

curr

edin

the

grou

pex

pose

dto

peni

cilli

nV

K(O

R1.

74;

95%

CI

0.83

–3.6

5)(n

otst

atis

tical

lyin

crea

sed)

.105

OR

for

cong

enita

lano

mal

ies

�1.

3(9

5%C

I1.

1–1.

6)in

aca

se-

cont

rols

tudy

(198

0–19

96)

of22

,865

infa

nts

with

cong

enita

lan

omal

ies

(173

[0.8

%]

trea

ted

with

peni

cilli

nV

duri

ngpr

egna

ncy)

.Adj

uste

dO

Rfo

rm

edic

ally

docu

men

ted

peni

cilli

nV

use

duri

ngth

e1s

ttr

imes

ter

show

edno

sign

ifica

ntas

soci

atio

nbe

twee

nm

ater

nale

xpos

ure

and

cong

enita

lan

omal

ies.

106

No

evid

ence

ofim

pair

edfe

rtili

tyor

harm

toth

efe

tus

due

tope

nici

llin

inre

prod

uctio

nst

udie

sin

mou

se,r

at,a

ndra

bbit

(Pro

duct

info

rmat

ion

Peni

cilli

nV

,199

7).

Incr

ease

dri

skof

tera

toge

nici

tyis

“non

e”ba

sed

on“g

ood”

data

.B

Rifa

mpi

nIn

am

eta-

anal

ysis

ofca

sere

port

s(1

971–

1977

;15

diffe

rent

auth

ors)

,111

cong

enita

lmal

form

atio

nsam

ong

410

offs

prin

gin

442

grav

idas

trea

ted

with

rifa

mpi

n—us

ually

inco

mbi

natio

nw

ithot

her

drug

s—w

as3.

3%an

dno

high

erth

anex

pect

edfo

rhu

man

popu

latio

ns.44

,107

Exp

osur

ew

asdu

ring

the

first

4m

onth

sin

109

case

s.T

hesp

onta

neou

sab

ortio

nra

te�

1.7%

was

belo

wex

pect

edfo

ra

gene

ralo

bste

tric

alpo

pula

tion.

108

In22

6w

omen

expo

sed

duri

ng22

9co

ncep

tions

,9of

fspr

ing

had

cong

enita

lmal

form

atio

nsam

ong

207

birt

hs(4

.3%

)37,1

09;

this

was

nogr

eate

rth

anth

ehi

stor

ical

rate

for

wom

enaf

flict

edw

ithtu

berc

ulos

is.37

,109

The

spon

tane

ous

abor

tion

rate

�2.

4%an

dw

asbe

low

expe

cted

for

gene

ralo

bste

tric

popu

latio

ns.10

8

No

cong

enita

lano

mal

ies

inth

eof

fspr

ing

of13

wom

entr

eate

dw

ithri

fam

pin

for

lepr

osy,

110

or18

wom

entr

eate

dfo

rbr

ucel

losi

s.11

1T

reat

men

toc

curr

eddu

ring

allt

rim

este

rs.

No

incr

ease

dra

teof

cong

enita

lan

omal

ies

inra

tsor

mic

etr

eate

dw

ith2.

5–10

times

the

usua

lhum

ando

se.11

2

Inra

tsan

dm

ice

trea

ted

with

�15

times

the

hum

ando

se(�

150

mg/

kgpe

rda

y),

ther

ew

asan

incr

ease

dra

teof

spin

abi

fida,

clef

tpa

late

,and

nono

ssifi

edsk

elet

alel

emen

ts(P

rodu

ctin

form

atio

nR

ifam

pin,

1971

).37,1

09T

hem

alfo

rmat

ion

rate

was

dose

-de

pend

ent.

No

incr

ease

inra

teof

cong

enita

lano

mal

ies

inra

bbits

trea

ted

with

sim

ilar

dose

s(2

00m

g/kg

per

day)

.N

ofe

talm

alfo

rmat

ions

inra

bbits

adm

inis

tere

ddo

ses

of50

mg/

kgpe

rda

yfo

r20

days

begi

nnin

gon

day

2.11

3

Inra

bbits

give

ndo

ses

ofup

to20

times

the

usua

lhum

ando

se,i

mpe

rfec

tos

teog

enes

isan

dem

bryo

toxi

city

wer

ere

port

ed(P

rodu

ctin

form

atio

nR

ifam

pin,

1971

).

Incr

ease

dri

skof

tera

toge

nici

tyis

“unl

ikel

y”ba

sed

on“l

imite

dto

fair

”da

ta.

“The

data

are

insu

ffici

ent

tost

ate

that

ther

eis

no[in

crea

sed]

risk

”.

C

(con

tinue

d)

1132 Nahum et al Antibiotic Use in Pregnancy OBSTETRICS & GYNECOLOGY

Tabl

e3.

Tera

toge

nic

and

Toxi

cPo

tent

ial

of

Elev

enB

road

-Sp

ectr

umA

ntib

ioti

csB

ased

on

Ava

ilab

leH

uman

and

Ani

mal

Dat

a(c

ont

inue

d)

Ant

ibio

tic

Hum

anD

ata:

Tera

toge

nic

and

Toxi

cEf

fect

sA

nim

alD

ata:

Tera

toge

nic

and

Toxi

cFe

tal

Effe

cts

Mag

nitu

de

of

Hum

anTe

rato

geni

cFe

tal

Ris

k(B

ased

on

TER

ISA

sses

smen

t)44

FDA

Preg

nanc

yC

ateg

ory

*

Van

com

ycin

No

cong

enita

lano

mal

ies

inth

eof

fspr

ing

of10

wom

enw

hore

ceiv

ed1

gq1

2ho

urs

IVfo

rat

leas

t1

wee

kdu

ring

eith

erth

e2n

dor

3rd

trim

este

r,w

ithpe

akan

dtr

ough

bloo

dle

vels

24.4

–65.

7�

g/m

Lan

d5.

6–16

.7�

g/m

L,r

espe

ctiv

ely.

42

No

cong

enita

labn

orm

ality

inth

ene

wbo

rnof

aw

oman

who

rece

ived

28da

ysof

1g

q12

hour

sIV

begi

nnin

gat

13w

eeks

ofpr

egna

ncy.

114

The

high

est

peak

leve

lmea

sure

dw

as20

�g/

mL

.A

feta

lbra

dyca

rdia

occu

rred

ina

preg

nant

wom

anw

hode

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VOL. 107, NO. 5, MAY 2006 Nahum et al Antibiotic Use in Pregnancy 1133

cokinetic data were available in lactating women forany of the antibiotics (Table 2).

CONCLUSIONThe safety of drug use in pregnancy is often anenigma. Many drugs have a long usage history inpregnancy without any controlled clinical trials everhaving been conducted to ascertain their safety orefficacy during human pregnancy. Although there islittle reason to believe that medications that havebeen demonstrated to be effective for particular con-ditions in nonpregnant subjects will not also proveeffective when delivered in proper doses to pregnantwomen, the changes in basic physiology that occur inthe maternal volume of distribution, renal clearance,and hepatic metabolism—as well as the potential forpharmacokinetic effects related to the distribution andmetabolism of the drug in the fetal compartment—make the issue of proper pregnancy-specific dosingdifficult to predict in the absence of empirical data. Tofurther complicate this issue, these physiologicchanges of pregnancy vary greatly from the first to thethird trimester.

Often, because of inadequate data regarding theprevalence of use, timing, and duration of exposure ofsufficient numbers of pregnant women to drugs, thereis insufficient information to formulate conclusivejudgments about their safety and efficacy that aredifferent from that for nonpregnant patients. Con-cerns regarding potential teratogenicity and fetal orneonatal toxicity are often incompletely addressed bythe limited amount of pregnancy and lactation expo-sure data and adverse event reports that are available.Because of this, conflicts can arise between the theo-retical fear of adverse fetal or neonatal consequencesand the general bias among most healthcare profes-sionals that the successful treatment of medical con-ditions in the mother is in the offspring’s best interest.This is especially true in the case of potentially

life-threatening illnesses, as is the case with manyagents of bioterrorism. These issues are particularlyrelevant to emergency response professionals, as wellas to primary health care providers who manage thepregnancies of the nearly four million women whodeliver newborns each year in the United States.2

The difficulty with the assessment of drug effects

Table 4. U.S. Food and Drug Administration Pregnancy Labeling Categories*

PregnancyCategory Category Description

A Well-controlled studies available in humans with no adverse effects observed in human pregnanciesB No adverse effects in well-controlled studies of human pregnancies with adverse effects seen in animal

pregnancies OR no adverse effects in animal pregnancies without well-controlled human pregnancy dataavailable

C Human data lacking with adverse pregnancy effects seen in animal studies OR no pregnancy data available ineither animals or humans

D Adverse effects demonstrated in human pregnancies; benefits of drug use may outweigh the associated risksX Adverse effects demonstrated in human or animal pregnancies; the risk of drug use clearly outweigh any

possible benefits

* Defined under 21 CFR 201.57 for the A, B, C, D, X Pregnancy Category system.

Table 5. Eleven Broad-Spectrum Antibiotics ThatMay Be Used in Pregnant and LactatingWomen in Cases of Exposure to PotentialAgent(s) of Bioterrorism4, 70,118-123

Antibiotic Potentially UsefulAgainst Bioterrorist

Agent(s)*

Amoxicillin Bacillus anthracis†

Chloramphenicol Bacillus anthracis†

Yersinia pestis†

Francisella tularensis†

Ciprofloxacin Bacillus anthracisYersinia pestis†

Francisella tularensis†

Coxiella burnetii†

Clindamycin Bacillus anthracis†

Doxycycline Bacillus anthracisYersinia pestisFrancisella tularensis

Gentamicin Bacillus anthracis†

Yersinia pestis†

Francisella tularensis†

Levofloxacin Bacillus anthracis†

Yersinia pestis†

Francisella tularensis†

Coxiella burnetii†

Penicillin G Bacillus anthracisPenicillin VK Bacillus anthracis†

Rifampin Bacillus anthracis†

Vancomycin Bacillus anthracis†

* As cited by the Centers for Disease Control and Prevention basedon in-vitro microbiologic susceptibility data from a limited set ofclinical isolates.

† Not currently a Food and Drug Administration–approved indi-cation.

1134 Nahum et al Antibiotic Use in Pregnancy OBSTETRICS & GYNECOLOGY

in pregnant women is typically related to a lack ofwell-controlled clinical data concerning the pharma-cokinetics and pharmacodynamics of their use inpregnancy. Assessments that pertain to rare adverseevents typically rely on the analysis of retrospectivecase-control data and, less often, on prospective co-hort series. By using these data, it is often possible toplace bounds on the risk of teratogenicity and fetal orneonatal toxicities that may result from medicationuse during pregnancy and lactation and to makereasonable judgments as to the safety of differentmedications, in addition to estimates concerning theirproper dosing. A summary of these findings—basedon the available data for 11 widely used broad-spectrum antibiotics—is presented in Tables 2 and 3.When indicated and properly administered, all ofthese agents seem to have sufficient evidence to allowfor their use during pregnancy and lactation.

Antibiotic use in pregnant and lactating womenhas become an increasing concern due to the threat ofbioterrorism. Because the timing and type of a biot-errorist attack is necessarily unpredictable, health careproviders must be aware of the different types ofdiseases and potential treatment options that may beneeded in these circumstances (Table 5). The situationis further complicated because the data that pertain tomedications for combating these agents are derivedprimarily from in vitro susceptibility studies in limitednumbers of clinical isolates that were obtained fromnonpregnant patients. Many of the treatment regi-mens that are currently recommended by the Centersfor Disease Control and Prevention for these bioter-rorist agents and their associated diseases are notcurrently FDA-approved indications because of thelack of adequate and well-controlled clinical trials tosupport their efficacy and safety under these circum-stances. Sometimes they may have been approvedbased on surrogate markers or endpoints (ie, 21 CFR314 Subpart H) or only animal data based on theanimal efficacy rule (ie, 21 CFR 314 Subpart I).124,125

Thus, the issues of teratogenicity and fetal toxicity, aswell as additional concerns surrounding the potentialneed for differential dosing of these drugs duringpregnancy under these circumstances, have an intrin-sically limited amount of data from which to draw.

The focus of this article has been to evaluate theexisting data within the public domain with regard to11 broad-spectrum antibiotics that can be of potentialuse in pregnant and lactating women. All are cur-rently available for the treatment of routine andlife-threatening bacterial infections, in addition toexposures associated with some known potentialagents of bioterrorism. In the unlikely case of a

bioterrorist attack, all health care providers must beable to provide their patients with appropriate treat-ment or prophylaxis after critical exposures. Pregnantand lactating women are a particularly vulnerablepopulation and health care professionals should befamiliar with the antibiotics that can be used undersuch adverse circumstances to feel confident in treat-ing such pathogenic exposures.

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