The Use of Dermatologic Drugs in Pregnancy and Lactation

Dermatol Clin

The Use of Dermatologic Drugs in Pregnancy and Lactation

Sancy A. Leachman, MD, PhDa,b, Barbara R. Reed, MDc,TaTom C. Mathews Jr. Familial Melanoma Research Clinic, Huntsman Cancer Institute, University of Utah,

2000 Circle of Hope, Suite 5242, Salt Lake City, UT 84112, USAbDepartment of Dermatology, University of Utah, Salt Lake City, UT 84112, USA

cUniversity of Colorado Health Sciences Center, 2200 East 18th Avenue, Denver, CO 80206, USA

Physicians of pregnant and nursing women are

wary of prescribing drugs given the often inadequate

data pertaining to indirect effects of drugs on fetuses

and nursing infants. Not all such effects are known or

even studied. When studies are available, their results

are often conflicting. Given the limits of pharma-

ceutical knowledge, doctors must ‘‘know what they

do not know’’ and proceed with due caution, making

judgment calls in the absence of secure data.

Although physicians of pregnant and nursing

patients are reluctant to provide dermatologic medi-

cations, many drugs display few or no apparent con-

traindications during pregnancy and lactation. Just as

awareness of the dangers of certain drugs or of the

limits of the data is important, so is awareness of the

documented safety of other drugs.

Reasons for avoiding the use of dermatologic

drugs during pregnancy and nursing are many. First,

because treatment of many dermatologic conditions

is elective, physicians and their patients prefer to wait

until after nursing ceases before treating certain

conditions. Second, because some drugs used by

the dermatologist have potentially harmful effects

on the mother, fetus, or nursing infant, physicians

are anxious to avoid harm. Third, because not every

pregnancy results in the delivery of a perfectly

healthy baby, physicians are concerned to avoid liti-

gation for having prescribed a medication that may be

deemed to have contributed to the problem. Clini-

cians treating dermatologic conditions often delay

0733-8635/06/$ – see front matter D 2006 Elsevier Inc. All rights

doi:10.1016/j.det.2006.01.001

T Corresponding author.

E-mail address: [email protected] (B.R. Reed).

pharmaceutical therapy until their patients have

ceased to nurse or have opted against nursing.

Reasons for choosing to use drug treatment during

pregnancy and nursing are as many as the needs of

patients suffering from skin conditions. Knowing that

a given drug has been well studied and can be used

without fear of harming mother, fetus, or nursing

infant aids the practice of dermatology.

This article compiles drug information allowing

the physician to make informed decisions regarding

dermatologic treatment. It identifies and discusses

indications and contraindications to various drugs to

the extent possible given available information.

When treatment with drugs presenting contraindica-

tions is essential, data must be carefully examined

and evaluated so that a risk-benefit ratio may be

determined in consultation with the patient. In cases

of significant risk, truly informed consent should be

obtained and documented.

To maximize ease of comparison of drug safety

during all of the phases of childbearing, information

is presented in this article by use of tables and

boxes (Tables 1–15 and Boxes 1–3). Table 1 pro-

vides a list of dermatologic agents that may interact

with contraceptives. Additional tables are categorized

by class of drug: analgesics, local anesthetics,

antibacterial agents, nonantibacterial antiacne prod-

ucts, antifungals, antihistamines, antiscabetics and

antipediculocides, antivirals, biologic agents, cortico-

steroids, topical immunomodulators, and miscellanea

(Tables 2,4,6–15). Each of the tables also lists the

U.S. Food and Drug Administration’s (FDA) preg-

nancy rating and the Teratogen Information Sys-

tem risk and data assessments (TERIS) along with

24 (2006) 167 – 197

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Table 1

Medications reportedly associated with contraceptive failure

Agent

Contraceptive

agent Proposed mechanism

Azathioprine Intrauterine

devices

Unknown

NSAIDS Intrauterine

devices

Unknown

Griseofulvin Oral

contraceptives

Increased estrogen

metabolism by hepatic

microsomal enzyme

induction

Rifampin Oral

contraceptives

Increased estrogen

metabolism by hepatic

microsomal enzyme

induction

or

Reduced enterohepatic

circulation of estrogens

Tetracyclinea Oral

contraceptives



Sulfonamidesa Oral

contraceptives



a Aside from CYP enzyme inducers (griseofulvin and

rifampin), significant controversy plagues other antibacterial

agents regarding a causal role in contraceptive failure.

leachman & reed168

warnings and comments. Other ratings and their

sources are included when available (see later for

background on the ratings). A discussion of the

importance of choosing or avoiding drug therapy in

relation to the phases of childbirth and a summary of

cautions aligned to those phases introduce the tables.

A set of four readily accessed lists of drugs of high

risk and of minimal risk is included.

Risk as related to the phases of childbearing

The phases of childbearing determine in large part

the choice or avoidance of given drug therapies in

treating all women patients of childbearing age and

a significant portion of a dermatologist’s practice.

Awareness of a patient’s individual periodicity, whose

phases include contraception, preconception, the

three trimesters of pregnancy, preterm, and lactation,

is essential. Cautions and contraindications change

according to temporal phase, requiring the dermatol-

ogist to stay apprised of the movement of a patient

from one phase to another.

The time before conception comprises the greatest

portion of the life of a woman of childbearing age and

yet is often overlooked. This phase itself is divided

into contraception and preconception. Some derma-

tologic drugs may interact with contraceptives

(Table 1) and may be contraindicated for use in pa-

tients who are seeking to avoid pregnancy. Other

drugs are contraindicated in those women seeking to

become pregnant or not avoiding pregnancy. Aspirin

and the nonsteroidal anti-inflammatory agents

(NSAIDs) ibuprofen and naproxen [1–4] offer prime

examples, increasing risk of miscarriage when taken

around the time of conception.

Pregnancy is distinguished by its three trimesters,

the last of which includes preterm. Some drugs

that are to be avoided during the first trimester are

safe to use during the latter two, such as certain

antibiotics of the cephalosporin family. Others may

be deemed safe throughout pregnancy, except in the

last 2 weeks when membrane rupture may put the

fetus at risk. Certain antihistamines may fall into this

category [5]. Table 2 and later in the text, the third

trimester or preterm section, provide more details

[5–25]. Drugs labeled as teratogenic may put a fetus

at risk for only a few weeks of pregnancy. Never-

theless, avoiding these drugs during the entire preg-

nancy is generally recommended.

The postnatal phase of nursing also affects treat-

ment choices. Drugs that place a nursing infant at risk

may be different from those that affect a fetus during

pregnancy. Ivermectin, which is teratogenic in ani-

mals at high doses and is excreted in breast milk, is to

be avoided throughout pregnancy pending further

human studies, yet use during lactation in third-world

nations has presented no identifiable problems for

infants [26,27]. NSAIDs are to be avoided during the

final trimester for reasons given later, but the Ameri-

can Academy of Pediatrics (AAP) lists them as

‘‘usually compatible’’ with lactation [6].

Differences in the type of preparation of a phar-

maceutical agent also may make for differences in

treatment options within a given phase of child-

bearing. The antifungal miconazole, for example, is

rated according to its topical and oral forms by

TERIS. In its topical form, miconazole is unlikely to

result in risk, whereas its risk in oral form is

undetermined [28]. The antibiotic clindamycin also

receives different ratings according to type of phar-

maceutical preparation and source. The AAP rates the

oral form as compatible with lactation [6] and a

manufacturer does not stipulate caution in oral use

[29]; the manufacturers of topical clindamycin, how-

ever, advise discontinuation until nursing has ceased

[30,31].

Before conception

Physicians prescribing a drug for women of child-

bearing age who are not pregnant or nursing should

Table 2

Antihistamines in pregnancy and lactation

Class Data [Ref.]

FDA

pregnancy

category

TERIS

Risk

Data

rating

Notes when

applicable

Antihistamines,

sedating

During lactation, use is contraindicated [8–10]

Controversy reigns over use of sedating

antihistamines during lactation

Briggs: probably compatible with lactation,

except doxepin, which has potential

toxicity [11]

AAP: no listing, except doxepin, whose

effect during lactation is unknown but may

be of concern [6]

USP DI: first-generation antihistamines have

anticholinergic effects and may inhibit

lactation; use of antihistamines is not

recommended because of risk of irritability

or unusual excitement in infants. If a sedating

antihistamine is chosen, mother should be

advised to stop if infant becomes jittery or

stops feeding well [12]

Cetirizinea By prescription in US; over-the-counter

in Canada

B Unlikely Limited

to fair

Insufficient

data to claim

no riskMetabolite of hydroxyzine

A small prospective study failed to determine

any increased fetal risk when used during

pregnancy [13]

Cyproheptadinea Not strictly an antihistamine, but used to

control itch

B Undetermined Limited High risk

is unlikely

Not been associated with problems during

pregnancy [14–16]

Manufacturer: no increased risk of

abnormalities throughout pregnancy, but

should be used ‘‘only when clearly

needed’’ [17]

No large studies demonstrate safety

Diphenhydraminea Long history of relatively uneventful use

during pregnancy [18]

B Undetermined Fair to

good

Insufficient

data to claim

no riskBriggs: avoid during last 2 weeks in case of

prematurity [8]

Antihistamine of choice for treatment of

pruritus during pregnancy among many

physicians

Use during pregnancy has been called

‘‘safe’’ [8]

Doxepina Systemic form has been associated with fetal

ileus close to term (mother had used a

phenothiazine compound also) [19]

Systemic =

unrated;

topical = B

Undetermined Limited —

In early pregnancy, no congenital human

malformations have been reported

Briggs: human data suggest low risk [11]

Topical form is associated with less risk than

oral form

During lactation, Briggs: potentially toxic [11]

AAP: effect during lactation is unknown

but may be of concern [6]

(continued on next page)

dermatologic drug use in pregnancy & lactation 169

Table 2 (continued)

Class Data [Ref.]

FDA

pregnancy

category

TERIS

Risk

Data

rating

Notes when

applicable

Fexofenadinea No human studies during pregnancy yet

conducted [20]

C Undetermined Very

limited

—

Manufacturer: benefits should outweigh

risks [20]

Briggs: no human data; animal data have

shown toxicity to embryo and fetus;

suggests that if oral antihistamine is needed,

chlorpheniramine or tripelanamine should

be considered; if these fail, cetirizine and

loratadine are considered acceptable [21]

AAP, Briggs: during lactation, thought to

be usually compatible [6,21]

Hydroxyzinea Briggs: a teratogen in animals given

multiples of human doses [22]

Unrated Unlikely Fair High risk

is unlikely

During early pregnancy, manufacturer:

use is contraindicated [23]

Some studies list as safe during

pregnancy [7,24]

Loratadine Briggs: during pregnancy, has been

associated with adverse outcomes (cleft

palate, microtia, microphthalmia, deafness,

dysmorphia, diaphragmatic hernia). No

clear relationship to use is established [25]

B Unlikely Fair High risk

is unlikely

Not thought to be teratogenic but, if an

oral antihistamine is required during

pregnancy, Briggs recommends

chlorpheniramine or tripelennamine as

first-line [25]

AAP, Briggs: during lactation, thought to

be usually compatible [6,25]

General warning: in a retrospective cohort study of 3025 infants of birth weight <1750 g, use of antihistamines during the last

2 weeks of pregnancy was associated with increased incidence of retrolental fibroplasia [5].a See also Antihistamines, sedating above.

Table 3

Pregnancy category D or unrated: drugs to avoid in

pregnancy and lactation

Drug Category D Unrated

Aspirina &

Azathioprine &

Bleomycin &

Colchicine &

Cyclophosphamide &

Griseofulvin &

Hydroxyurea &

Mechlorethamine &

Penicillamine &

Potassium iodide &

Spironolactone &

Tetracycline &

a High-dose, extended-release form should be avoided.

leachman & reed170

have several concerns: (1) contraceptive failure

caused by medication interactions, (2) potential risk

to mother and fetus caused by the drug should preg-

nancy occur, (3) possible interference with concep-

tion, (4) potential risk of spontaneous abortion.

Moreover, in a few cases, treatment of men anticipat-

ing pregnancy must be approached cautiously.

Some medications have been associated with a

possible risk of contraceptive failure (see Table 1).

Azathioprine [32] and NSAIDs [33], for example,

have been associated with increased risk of contra-

ceptive failure of the intrauterine device. Oral contra-

ceptive failure may occur when the oral contraceptive

is taken along with hepatic enzyme inducers, such as

griseofulvin [34], which may increase metabolism of

estrogen (including oral contraceptives) because of

induction of hepatic microsomal enzymes. Other oral

Table 4

Topical nonantibacterial antiacne products in pregnancy and lactation

Class Data [Ref.]

FDA

pregnancy

category

TERIS

Risk

Data

rating

Notes when

applicable

Azelaic acid Has not shown mutagenicity, teratogenicity,

or embryotoxicity in animals [62]

B Unrated — —

Minimal absorption occurs

Therefore small doses unlikely to pose

risk during pregnancy

A manufacturer: data is too limited to

assess safety [63]

USP DI, a manufacturer: no problems

reported during lactation [63,64], though

may be absorbed in small amounts

Benzoyl

peroxide

USP DI: may be systematically absorbed C Undetermined None High risk of

congenital

anomalies is

unlikely; small

risk cannot be

excluded

Human studies have not been conducted [65]

During pregnancy, not contraindicated [66]

USP DI, manufacturer: no problems reported

during lactation [67,68], though may be

absorbed in small amounts

Clindamycin See Antibacterial agents (Table 8) — — — —

Erythromycin See Antibacterial agents (Table 8) — — — —

Metronidazole Oral form has not been associated with

congenital anomalies in animals [69], or in

humans when used in the first [56–58] or

last [59,60] trimesters

Oral = B Oral vaginal

drug: unlikely

Good —

Throughout pregnancy, no contraindication

of topical use

Manufacturers: ‘‘only if clearly needed’’

for topical and vaginal forms [70,71]

During lactation, topical form is unlikely

to be absorbed in significant amounts.

USP DI does not contraindicate use during

lactation [69], although some manufacturers

do [70,71]

Retinoids,

adapalene

Very low systematic absorption. C Unrated — —

A congenital anomaly of the eye was

reported in association with use [72]

Manufacturer advices potential maternal

benefit should be weighed against potential

infant risk during pregnancy [73]

Briggs: doubtful that absorption might

represent any risk to the infant during

lactation [74]

Retinoids,

isotretinoin

FDA: can cause birth defects in human

beings [61]

X

In 2006, special registration is required to

dispense or use [61]

Retinoids,

tazarotene

Absorbed minimally [39,40] X Undetermined Very

limited

High risk

is unlikelyCaused retinoid-like anomalies in

animals [41]

Thus manufacturer recommends negative

pregnancy test within 2 wk before

treatment [41]

During lactation, risk not known, but has

been contraindicated [41]



Table 4 (continued)

Class Data [Ref.]

FDA

pregnancy

category

TERIS

Risk

Data

rating

Notes when

applicable

Retinoids,

tretinoin

During first trimester, associated with

teratogenicity [75–77], but a controlled

study failed to confirm [78]

C Unlikely Fair —

One study, assuming maximal absorption,

estimated the 1 g/d of 0.1% preparation

would result in serum levels of <15% of

the vitamin A from a standard prenatal

vitamin A preparation [79]

Given availability of alternatives, avoid

during first trimester

No problems reported in infants of mothers

treated after first trimester

During second and third trimesters, use

may be considered in consultation with

patient and her obstetrician to avoid

misunderstanding

One article argues for safety of use during

pregnancy [7]

Minimal amounts found in breast milk are

not thought to be harmful to lactating

infants [80]

During lactation, animal studies show no

adverse effects [79,81]

leachman & reed172

medications that may reduce oral contraceptive effec-

tiveness include rifampin [35], which may stimulate

estrogen metabolism or reduce enterohepatic circu-

lation of estrogens, and penicillins [36], which also

reduce enterohepatic circulation of estrogens. Tetra-

Table 5

U.S. Food and Drug Administration pregnancy risk

categories

Category Definition

X Contraindicated in pregnancy

No reason to risk use of the drug in

pregnancy

D Positive evidence for risk to human fetus

Benefits, however, may outweigh risks of

the drug

C Risk cannot be ruled out; human studies

are lacking

Animal studies may or may not show risk

Potential benefits may justify potential risk

B No risk to human fetus despite possible

animal risk

No risk in animal studies; human studies

have not been done

A Controlled studies show no fetal risk

Unrated No pregnancy category has been assigned

cyclines [37] and sulfonamides [38] may increase

breakthrough bleeding and reduce contraceptive

effectiveness, although this is quite controversial. Al-

though the retinoid tazarotene is absorbed minimally

[39,40], its manufacturer recommends a negative

pregnancy test within 2 weeks before treatment, be-

cause it has caused retinoid-like anomalies in ani-

mals [41].

Both men and women should avoid methotrexate

[42] if pregnancy is anticipated. Although there are

no published studies implicating thalidomide in the

production of congenital anomalies when men use it

around the time of conception, the manufacturer [43]

and U.S. Pharmacopeia Drug Information (USP DI)

[44] recommend that men taking thalidomide use a

latex condom during intercourse.

First trimester

During very early pregnancy, encompassing the

first 2 to 2.5 weeks of gestation (4–4.5 weeks after

the first day of the last normal menstrual cycle), cells

are undifferentiated. Drugs administered during this

period tend to affect all cells equally, resulting in

most cases in either a terminally toxic event or an

uneventful continuation of life. That is, the net

Table 6

Analgesics in pregnancy and lactation

Class Data [Ref.]

FDA

pregnancy

category

TERIS

Risk

Data

rating

Notes when

applicable

Acetaminophen Analgesic of choice in pregnancy B None to

minimal

except at

toxic dose

Good —

Briggs: during pregnancy, high dose

caused severe anemia in one mother; infant

died of renal problems. Overdose may result

in hepato- or nephrotoxicity in infant or

mother. Low dose not linked with

identifiable risk throughout pregnancy [99]

Briggs: May be used during lactation [99]

Aspirin Known animal teratogen C None to

minimal for

occasional

low dose

Fair to

good

—

Extended-dose, Briggs: D rating [45]

Low-dose: No appearance of teratogenicity.

High-dose, Briggs: Anomaly increase in

animals; no consistency in anomalies in

humans. Avoidance recommended [45]

Many studies show prevention of fetal

growth retardation, pregnancy-induced

hypertension, stillbirth [100]

Time of conception: increased risk of

miscarriage [1,2]

Final trimester: fetal or neonatal

hemorrhage [101,102] and premature

closure of ductus arteriosus [103] are

greatest concerns. Also postmaturity

syndrome [104], gastroschisis [105]

Briggs: human data are limited: potential

toxicity during lactation [45]

AAP: recommends avoidance during

lactation, given possible association with

Reye’s syndrome [6]

Low dose: Infant of lactating mother using

aspirin presented dose-related metabolic

acidosis; serum salicylate level was

24 mg/dL. No maternal milk or serum

salicylate levels were obtained [106]

NSAIDs,

ibuprofen

Known to block blastocyst implantation in

animals [107,108]

B Minimal Fair Final trimester:

neonatal renal

failure; premature

closure of ductus

arteriosus;

consequent risk

to perinatal

adaptation;

oligohydramnios

Low dose, first trimester: increased risk of

spontaneous abortion [1–4]

Briggs, final trimester: avoid because of

increased risk of cardiovascular and

pulmonary dysfunction, oligohydramnios [45]

AAP: ‘‘Usually compatible’’ with

lactation [6]

NSAIDs,

naproxenaB Undetermined Limited Just before

delivery: may be

associated with

abnormalities

of neonatal

cardiovascular

adaptation



Table 6 (continued)

Class Data [Ref.]

FDA

pregnancy

category

TERIS

Risk

Data

rating

Notes when

applicable

Opioid

narcotics,

general

May be used for very short periods in

small amounts

— — — —

Low dose: except for morphine, not

associated with teratogenicity in

isolated use

Greatest risks: respiratory depression from

high dose near time of delivery withdrawal

symptoms after chronic maternal use.

Excreted in low amounts through lactation

Opioid

narcotics,

codeineb

Briggs: high dose, during pregnancy,

inconsistent congenital malformations have

suggested association with fetal risk [109]

C Unlikely Fair to

good

—

High dose, late in pregnancy: as in use by

addicts, has been associated with

development of withdrawal symptoms in

infants [110]

AAP lists as compatible with lactation [6]

Opioid

narcotics,

meperidineb

AAP lists as compatible with lactation [6] C Unlikely Fair —

Opioid

narcotics,

morphineb

USP DI: not reported to be a teratogen,

except at high dose in animals [111]

C Congenital

abnormalities:

unlikely;

Fair to

good

—

Low dose: in occasional doses, not thought

to cause problems in children. However,

animal studies show persistent problems in

offspring exposed in utero [112,113]

Neonatal

neurobehavioral

defects:

moderateSignificant withdrawal syndrome in infants

of addicted mothers [114]


Opioid

narcotics,

oxycodoneb

AAP: compatibility with lactation has not

been rated

C Undetermined Limited —

Opioid

narcotics,

propoxypheneb

Briggs: associated with occasional

congenital abnormalities, though relation to

the anomaly is thought to be spurious [115]

C None Good —

Chronic maternal use has produced

long-lasting behavioral abnormalities in

infants [116]

High Dose: Chronic maternal use has

produced withdrawal symptoms in infants.

Risk of overdose to infant is unknown

[117,118]


a See NSAIDs, ibuprofen above.b See also Opioid narcotics, general above.

leachman & reed174

negative effect tends to be spontaneous abortion

rather than the production of any congenital anoma-

lies. Animal studies reflect this finding as toxicity,

which is considered to be a potentially adverse out-

come of pregnancy in the current FDA pregnancy

categories. Human toxicity studies are not done,

because of difficulties in performing ethical drug

studies in this population.

Organogenesis lasts from 2 to 8 weeks of ges-

tation of the pregnancy (weeks 4–10 after the first

Table 7

Local anesthetics in pregnancy and lactation

Class Data [Ref.]

FDA

pregnancy

category

TERIS

Risk Data rating

Notes when

applicable

Lidocaine No contraindication to use during pregnancy B None for local

administration

Fair —

In doses used for small excisional biopsies,

poses no appreciable risk to mother or fetus

AAP, Briggs: may be used during lactation

[6,120]

Lidocaine

with

epinephrine

No contraindication to use during pregnancy B Unlikely for use

of therapeutic doses

of epinephrine

Fair —



Lidocaine-

prilocaine

No contraindication to use during pregnancy B Undetermined for

local administration

of prilocaine

Very

limited

—




day of the last menstrual cycle). At this stage, cells

begin to specialize and may be differentially affected

by particular drugs, resulting in congenital anomalies.

Avoiding all medications known to have possible

teratogenic effects in these weeks is especially im-

portant. Under this category are included all medi-

cations listed as FDA pregnancy category X or D,

and some drugs with higher ratings or drugs that are

unrated. In animal models, aspirin (with a B rating)

has been found to block implantation in the blastocyst

phase, and NSAIDs (with C ratings) have been asso-

ciated with spontaneous abortions and possibly with

congenital malformations (Table 5) [45]. Exceptions

on an individual basis may be considered when use

is essential. For example, the standard of care for

pregnant women suffering from antiphospholipid

syndrome, who are at higher risk of pregnancy loss,

fetal death, preeclampsia, and placental insufficiency,

is low-molecular-weight heparin in combination with

low-dose aspirin [46–48]. A list of medications that

have been most clearly established as teratogenic is

included in Table 3 and Box 1.

Second trimester

In midpregnancy, fetal development may be af-

fected by maternal drug use as maturation of various

organ systems occurs. For example, dentition is af-

fected by tetracycline, which is well known to pro-

duce dental staining and enamel hypoplasia [49–51]

because of its binding with calcium. Spironolactone,

used for treatment of adult-onset acne in women, has

been associated with feminization of male fetuses, in

particular of their external genitalia, in an animal

study [52].

Drug metabolism by the fetus may occur at a rate

different from that of the mother. If fetal metabolism

is lower than maternal metabolism, removal is slower

and results in prolonged exposure while levels of

the agent at any given time are higher, leading to

potential harmful consequences. An example is ma-

ternal iodide use, which may result in fetal hypo-

thyroidism [53,54].

Drug excretion by the fetus into amniotic fluid

may theoretically promote prolonged exposure by

virtue of skin contact with amniotic fluid or through

amniotic fluid ingestion by the infant. No known

examples are available.

In most cases, the second trimester is not singled

out in the ratings used as peculiarly affected by the

use of dermatologic drugs. Rather, it usually is

coupled with the first trimester or the third trimes-

ter when any distinction of periodicity within the

9 months of pregnancy is indicated. Silver sulfa-

diazine, for example, is thought to pose potential

risk during the third trimester but not the second.

Here, the worry is that kernicterus or hemorrhage

may occur in a premature or glucose-6-phosphate

dehydrogenase-deficient infant [55]. The retinoid

tretinoin, however, is cautioned against during the

first trimester, because of its association with tera-

togenicity, but no problems have been reported in

infants of mothers treated during second and third

trimesters. Use of tretinoin, a C-category drug, may

be considered during those trimesters, but consul-

tation with the patient’s obstetrician is advised.

Tretinoin’s rating should not be confused with the

X-category isotretinoin, marketed under several

trade names. See the section on ratings later for

further discussion of isotretinoin.

Table

8

Antibacterial

agentsin

pregnancy

andlactation

Class

Data[Ref.]

FDA

pregnancy

category

TERIS

Risk

Datarating

Noteswhen

applicable

Azithromycin

Chem

ically

relatedto

erythromycin

BUndetermined

Verylimited

—

Briggs:duringpregnancy,noassociationwithareported

risk

[120]

Briggs:duringlactation,use

withcaution[120]

Bacitracin

Has

notbeenassociated

withteratogenicity.

Unrated

Undetermined

None

—

Small-dose

use

has

notbeenassociated

withrisk

tothefetus,though

largestudieshavenotbeenconducted

Cephalosporins,general

Insecondandthirdtrim

esters,noproblemsin

fetusidentified.

——

——


withcaution[121,122]

Cephalosporins,cefaclor

Briggs:duringfirsttrim

ester,an

associationwithcongenital

malform

ationswas

foundin

onelargesurveillance

study[121]

BUndetermined

Verylimited

—

Cephalosporins,cefadroxila

Briggs:in

firsttrim

ester,nofindingofassociationwithcongenital

malform

ations[122]

——

——

Cephalosporins,cephalexin

aBriggs:duringfirsttrim

ester,an


malform

ationswas

foundin


study[121]

BUndetermined

Poor

—

Cephalosporins,cephradinea

Briggs:duringfirsttrim

ester,an


malform

ationswas

foundin


study[121]

BUnlikely

Lim

ited

tofair

—

Clindam

ycin

Has

notbeenassociated

withteratogenicity

BOraluse:

undetermined

Lim

ited

Highrisk

is

unlikely

Has

beenassociated

withpseudomem

branouscolitis,thoughrisk

is

notincreasedduringpregnancy

[123]

Small-dose

use

has

notbeenassociated

withrisk

tothefetus,though


Inlactatingmother,bloodystoolsreported

inan

infant,butetiology

was

notproven

[124]

AAPratesoralform

ascompatible

withlactation[6]

Amanufactureroftheoralform

does

notcautionagainstsuch

use

[29];

butmanufacturers

ofthetopical

form

advisediscontinuation[30,31]

Dapsone

Has

beenusedduringpregnancy

fortreatm

entofleprosy

[125]

CUndetermined

Verylimited

—

Literature

supportssafety

duringpregnancy

fortreatm

entofleprosy

anddermatitisherpetiform

is[84–86]

Briggs:duringpregnancy,nomajorfetalrisk

[87]

Last

month

ofpregnancy:stoppingtreatm

entmay

minim

izea

theoreticrisk

ofneonatal

kernicterus[88]

Briggs[87],USPDI[86],andthemanufacturer[126]adviseagainst

use

duringlactation,butAAPclaims‘‘usually

compatible’’[6]

leachman & reed176

Erythromycinand

relatedmacrolides

Throughoutpregnancy,oralantibioticofchoice,

alongwith

penicillins.Exceptforerythromycinestolate,noreported

risk

Oral=B

Oralform

:none

Good

—


oralform

withcaution[127]

Topical=B

orC

Duringfirst2weeksoflife,oralform

associated

withincreased

risk

ofpyloricstenosis[128]

Topical

form

has

notbeenassociated

withteratogenicity

Topical

form

may

beusedduringpregnancy.

Briggs:topical

form

iscompatible

withlactation[127]

AAPhas

noratingfortopical

form

duringlactation

Erythromycinestolate

Usedlonger

than

3weeks,has

beenassociated

withasubclinical

maternal

hepatoxicityandshould

beavoided

[129–131]

Fluoroquinolones:

ciprofloxacin

ofloxacin

levofloxacin

lomefloxacin

norfloxacin

enoxacin

trovafloxacin

sparfloxacin

nalidixic

acid

Duringpregnancy,congenital

anomaliesareinconsistent[132–134];

use

asafirst-linedrugisnotadvised

All=C

Ciprofloxacin:

unlikely

Fair

Insufficientdata

toclaim

norisk

Briggs:accidentaladministrationshould

notbean

indicationfor

abortion[135]

Listedas

probably

compatible

withlactation.However,manufacturer

advises

discontinuationofciprofloxacin

because

ofpotential

of

seriousadverse

reactionsin

infant[91]

Duringlactation,USPDIrecommendsavoidingunless

noalternate

may

beprescribed

[92]

Mupirocin

Has

notbeenassociated

withteratogenicity

BUndetermined

None

—

Small-dose

use

has

notbeenassociated

withrisk

tothefetus,though


Neomycin

Has

notbeenassociated

withteratogenicity

Unrated

Undetermined

——

May

beusedduringpregnancy

Penicillins

Throughoutpregnancy,antibioticofchoicealongwitherythromycin

CNone

Good

—

Duringpregnancy,use

notcontraindicated

Beta-lactam

antibacterial

agentsofthepenicillinfamilyhavenotbeen

associated

withan

increasedrisk

ofcongenital

anomalies

Briggs:penicillinG,penicillinV,am

oxicillin,am

picillin,dicloxacillin

areunlikelyto

beteratogenic

[136]

PDR:penicillinG

benzathineandpenicillinG

procaineisexcreted

in

breastmilk.Use

cautionduringlactation[127]

Polymyxin

BHas

notbeenassociated

withteratogenicity

Unrated

Undetermined

None

—

Small-dose

use

has

notbeenassociated

withrisk

tothefetus,though


(continued

onnextpage)


Table

8(continued)

Class

Data[Ref.]

FDA

pregnancy

category

TERIS

Risk

Datarating

Noteswhen

applicable

Sulfonam

ides,oral

sulfam

ethoxazole

trim

ethoprim

Briggs:possible

associationwithincreasedrisk

ofcongenital

abnorm

alitiesisdocumented[82]

CSulfam

ethoxazole:

unlikely

Sulfam

ethoxazole:

limited

tofair

Sulfam

ethoxazole:

highrisk

isunlikely

Duringearlypregnancy,use

notcontraindicated,yet

alternatives

havebetterdataindicatingnorisk.

Trimethoprim:sm

all

Trimethoprim:good

Trimethoprim:

risk

reducedin

women

takingfolic

acid

duringfirst

trim

ester

Duringlactation,pose

apotential

risk

ofhem

olysisin

glucose-

6-phosphatedehydrogenase(G

6PD)-deficientnew

borns[138,139]

Silver

sulfadiazine,

topical

USPDI:duringlate

thirdtrim

ester,use

thoughtto

pose

potential

risk

forkernicterusandhem

orrhagein

premature

infantorinfant

withG6PD

deficiency

[55].Thoughrisk

may

betheoretic,

an

alternatetopical

antibioticispreferred

BUnlikely

Poorto

fair

—

AAP,

USPDI:duringlactation,use

isdiscouraged

ifinfanthas

jaundiceorG6PD

deficiency

[6,55]

Sulfur,topical,withor

withoutsodium

sulfacetam

ideor

resorcinol

Has

notbeenassociated

withkernicterus

CNone

Poorto

fair

—

Duringpregnancy,notcontraindicated

Compatible

withlactation[140,141]

AAPhas

noratingforuse

duringlactation

Tetracyclines,general

Duringearlypregnancy,use

notassociated

withcongenital

anomalies[142,143]

DCongenital

abnorm

alities:

noneto

minim

al

Congenital

abnorm

alities:fair

—

Duringsecondorthirdtrim

esters,risk

ofdentalstainingand

enam

elhypoplasia[49–51]

Dentalanomalies:high

Dentalanomalies:

excellent

Duringlactation,system

atic

use

iscontroversial.

AAPstates

that

use

iscompatible

withlactationbecause

of

negligible

absorption[6]

Tetracyclines,minocyclineb


esters,notadvised

given

structural

similarityto

tetracycline[49–51]

DCongenital

abnorm

alities:

undetermined

Congenital

abnorm

alities:

verylimited

—

Duringlactation,black

milkhas

beenreported

[144]

Tetracyclines,doxycyclineb


esters,notadvised

given

structural

similarityto

tetracycline[49–51]

DCongenital

abnorm

alities:

unlikely

Congenital

abnorm

alities:

limited

tofair

—

Dentalanomalies:

undetermined

Dentalanomalies:

limited

tofair

aSee

alsoCephalosporins,general

above.

bSee

alsoTetracyclines,general

above.

leachman & reed178


Because of absence of relevant data, one example

against the rule of the nonsingularity of the second

trimester is the oral form of metronidazole. Another

antiacne drug, oral metronidazole has not been asso-

ciated with congenital anomalies in human beings

when used in the first [56–58] and third [59,60]

trimesters. This is not to say that congenital anoma-

lies are associated with its use in the second trimes-

ter, but other choices may be preferred given the

lack of data specific to the second trimester (Table 4)

[39–41,56–81].

Third trimester and preterm

Late in pregnancy, especially near the time of

delivery, nonteratogenic conditions may occur. Such

drugs as sulfonamides, which may produce risk in

infants who are premature [82], and NSAIDs, which

may promote persistent fetal circulation or oligohy-

dramnios [83], are to be avoided. As in other phases

of pregnancy, studies can be conflicting. For exam-

ple, dapsone is supported in the literature as safe

during pregnancy for treatment of leprosy and der-

matitis herpetiformis [84–86] and Briggs and co-

workers [87] state that its use poses no major risk to

the fetus during pregnancy, yet one article claims

that, in the last month of pregnancy, stopping treat-

ment with dapsone minimizes a theoretic risk of neo-

natal kernicterus [88].

Keeping in mind that a drug may be dangerous in

one phase, while safe in another, is crucial to the

treatment of women in their third trimester. From the

second trimester to the rupture of the membrane,

topical clotrimazole has not been associated with ad-

verse effects, whereas during the first trimester, oral

or topical use of clotrimazole for treatment of vagi-

nitis has been associated with a slightly increased risk

of human congenital defects [89] (although Briggs

and coworkers [90] state that the association is not

supported by the data).

Awareness of the due date of the maternal pa-

tient is especially important to treatment. Antihis-

tamines provide a prime example. In a retrospective

cohort study of 3025 infants with birth weight of

less than 1750 g, use of antihistamines during the

last 2 weeks of pregnancy was associated with an

increased incidence of retrolental fibroplasia [5].

Findings regarding the antifungal clotrimazole ex-

emplify the occasional need for subtle distinction-

making in prescribing drugs during the final weeks

of pregnancy. Although use of clotrimazole in the

third trimester has not been associated with prob-

lems, studies neither indicate nor contraindicate its

safety in use after the membrane breaks [90].

Lactation

Nearly all adverse effects in nursing infants have

occurred during the first 6 months of life. Sedation

and diarrhea are easy to detect. Less apparent are

possible neurotoxic effects. In general, use of drugs

known to be teratogenic is not advised during lac-

tation (see Table 1 and Box 1). This includes all reti-

noids and antineoplastic agents.

As with pregnancy, findings regarding the use of

dermatologic drugs during breast-feeding are some-

times controversial and require weighing the evi-

dence carefully. Ratings of a single drug may differ.

The antibiotic family of fluoroquinolones, for exam-

ple, is listed as probably compatible with lactation,

yet the manufacturer of ciprofloxacin advises dis-

continuation of breast-feeding while using fluoro-

quinolones given the potential of serious adverse

reactions in the infant [91]. The USP DI recommends

avoiding fluoroquinolones during lactation unless an

alternative antibiotic cannot be prescribed [92].

Many women elect to avoid exposure to all drugs,

fearing some as yet undiscovered problem. The

physician should be aware and respectful of this

wish while being able to advise patients of drugs that

place them and their babies at minimal risk. Further,

physicians should be mindful that treatment of some

dermatologic conditions, such as onychomycosis, can

be safely deferred until the completion of pregnancy

and lactation.

Ratings used in drug tables and other sources

Several ratings are available to assist physicians

in determining the relative safety of dermatologic

drugs to the fetus or nursing infant and in recognizing

the existence of conflicting opinion in the absence of

solid data or the presence of probable bias. The tables

in this article provide two catalogs of risk. The FDA

pregnancy categories can be located in the Physi-

cians’ Desk Reference under the product information

list supplied by drug manufacturers [93]. The TERIS

is available on-line by subscription [28]. In addition,

several other rating sources are also used. Drugs in

Pregnancy and Lactation is a regularly updated

textbook reviewing the risks of using drugs during

pregnancy and lactation [94]. The AAP [6] reviews

information on effects of drugs on lactation, publish-

ing an updated rating list every several years. The

USP DI has compiled three volumes on the use of

drugs and includes indications and contraindications

during pregnancy and lactation [95].

Table

9

Antifungal

agentsin

pregnancy

andlactation

Class

Data[Ref.]

FDA

pregnancy

category

TERIS

Risk

Datarating

Noteswhen

applicable

Butaconazole,topical

Has

notbeenstudiedin

humans

CUnrated

——

Noassociationreported

withproblemsduringpregnancy

Ciclopirox,topical

Has

notbeenstudiedin

humans.

B—

——



Clotrim

azole,topical

Duringfirsttrim

ester,fororalortopicaltreatm

entofvaginitis,has

been

associated

withaslightlyincreasedrisk

ofhuman

congenital

defectsin

onestudy[89]

BUnlikely

Lim

ited-to-fair

Datainsufficientto

claim

norisk

Briggs:associationofvaginal

treatm

entandcongenital

defectsisnot

supported

bydata[90]

From

secondtrim

esterto

mem

branerupture,topicaluse

has

notbeen

associated

withadverse

effects

Econazole,topical

Duringfirsttrim

ester,manufacturerrecommendsuse

only

when

essential

towelfare

ofthemother

[145]

C—

——

Close

toterm

,topical

administrationofintravaginal

yeastmedications

isnotadvised,given

risk

ofuterinecontaminationaftermem

brane

rupture

[146]

Fluconazole

Inhighdoses,has

beenassociated

withhuman

malform

ations

[147–149]

CLow,single,

oraldose:unlikely

Low,single,oral

dose:fairto

good

Alow

single

oraldose

isunlikelyto

pose

a

substantial

risk

Briggs:duringfirsttw

otrim

esters,pendingfurther

inform

ation,

electiveuse

ofprolonged

doses(>400mg/d)should

beavoided

[150]

Duringpregnancy,single-dose

use

does

notappearto

beassociated

withincreasedrisk

tofetus[150]

Highdose

chronic

use:undetermined

Highdose

chronic

use:limited

tofair

Manufactureradvises

againstuse

duringlactation[151]

Briggs,AAP:compatible

withlactation[6,150]

Griseofulvin

Several

reportsim

plicate

use

asapossible

etiologyforconjoined

twins

[152,153].Noother

congenital

anomalyisreported

Unrated

Undetermined

Lim

ited

Highrisk

isunlikely;

smallrisk

cannot

beexcluded

Briggs:anim

alstudiesshow

increasedfrequency

offetaldeath,growth

retardation,andskeletal

anomalies.Significance

tohuman

use

unknown[154]

Before

andduringearlypregnancy,manufacturers

thusrecommend

avoidance

[155,156]

Briggs:duringlactation,compatible

[154]

leachman & reed180

Itraconazole

Showed

dose-related

embryotoxicityandteratogenicityin

rodents,

thoughtto

bebecause

ofadrenal

effects[157]

CUnlikely

Lim

ited

tofair

—

Usedsafely

inareported

pregnancy

[158]

USPDI:risk

ofhuman

teratogenicityisthoughtto

thelowestofthe

system

icazole

antifungal

agentssince,in

contrastto

fluconazole

and

ketoconazole,little

effect

onsteroid

horm

ones

[159]

Duringfirsttrim

ester,Briggs:avoid,given

that

fluconazole

has

been

responsible

formalform

ations[160]

Duringlactation,Briggs:has

potential

toxicity[160]

Ketoconazole

Oralform

has

beenassociated

withhuman

[161]andanim

al[162]

teratogenicity;topical

form

has

notbeenstudiedin

humans.

Oral=

BOralform

:

undetermined

Oralform

:limited

—

Oralform

should

beavoided,especiallyduringfirsttrim

ester[161,162]

Topical=C

Topical

form

:

undetermined

Topical

form

:

verylimited

Oralform

associated

withim

pairm

entofprogesteronesecretionand

preventionofim

plantationin

rats,indicatingpossible

interference

withearlypregnancy

[163]

Noproblemsin

use

oftopical

form

reported

duringpregnancy

Briggs:topical

form

isprobably

compatible

withpregnancy

[164]

Manufacturer:recommendsagainstuse

ofsystem

icandtopical

form

s

duringlactation,thoughnodataverifyingproblemsin

use

oftopical

form

[165,166]

Briggs:system

icform

iscompatible

withlactation;topical

form

is

probably

compatible

[166]

Miconazole

Associated

withanim

alfetotoxicity

CTopical

form

:

unlikely

Topical

form

:

fairto

good

Oralform

:data

insufficientto

claim

norisk

Briggs:datadonotsupportassociationwithcongenital

defects[167]

Oralform

:

undetermined

Oralform

:limited

Naftifine,

topical

Has

notbeenstudiedin

humans

B—

——



Nystatin

Associated

withnoknownrisk

tofetusduringpregnancy

[168,169]

BOralform

:none

Fairto

good

—

Topical

form

has

notbeenstudiedin

humans

Briggs:throughoutpregnancy,nocontraindicationto

use

oforal

form

[170]

Oxiconazole,topical

Has

notbeenstudiedin

humans

B—

——



Selenium

sulfide,

topical

Manufactureradvises

againstuse

duringpregnancy

fortreatm

entof

tinea

versicolor,because

noanim

alorhuman

studieshavebeen

conducted

andthusrisk

tofetusisunknown[171]

Ca

Undetermined

None

Highrisk

isunlikely;

smallrisk

cannot

beexcluded

Duringlactation,onemanufacturerrecommendsagainstuse

over

large

areasfortreatm

entoftinea

versicolor[171]

(continued

onnextpage)


Table

9(continued)

Class

Data[Ref.]

FDA

pregnancy

category

TERIS

Risk

Datarating

Noteswhen

applicable

Sulconazole

Has

notbeenstudiedin

humans.

C—

——



Terbinafine

USPDI:anim

alstudies(oralform

)in

pregnancy

show

tumorogenicity

(productionofbenigntumors)butnotfetalloss

(anim

altoxicity)[172].

BUnrated

——

Nohuman

studieshavebeendoneoforalortopical

form

s

Nocase

reportsoftopical

use

associated

withproblems

duringpregnancy

Briggs,oralform

:anim

aldatasuggestlow

risk;nohuman

dataare

available

[173]

Manufactureradvises

againstelectiveuse

oforalform

during

pregnancy

fortreatm

entofonychomycosis[174]

Briggs:system

icform

has

potential

toxicityduringlactation;topical

form

isprobably

compatible

[173]

USPDI:should

notbeapplied

tobreasts[172]

Manufactureradvises

against

use

ofsystem

ic[174]andtopical

[175]

form

sduringlactationthoughnodataverifyproblemsin

use

of

topical

form

Tioconazole,topical

Has

notbeenstudiedin

humans

C—

——



Voriconazole

Aknownteratogen,avoid

duringpregnancy

[176]

DUnrated

——

Manufacturerrecommendsagainstuse

duringlactation[176]

aFortinea

versicolor.

leachman & reed182

Table 10

Antiscabetics and antipediculocides in pregnancy and lactation

Class Data [Ref.]

FDA

pregnancy

category

TERIS

Risk Data rating

Notes when

applicable

Crotamiton No studies of human absorption C Undetermined None —

During pregnancy, no adverse effects have

been reported

During lactation, no documentation

of problems

Ivermectin Teratogenic in animals at high doses. C Unrated — —

Human teratogenicity, toxicity have not

been observed [177]

Use for scabies is not FDA-approved

Avoid during pregnancy, pending

further study

Excreted during lactation. Use in large

third-world populations shows no

identifiable problems for infants [26,27]

Lindane Controversial, with both discouraging

[178,179] and encouraging [180,181]

reports

B Undetermined Limited High risk is unlikely; sub-

stantial risk in doses high

enough to be toxic to

pregnant womenAdverse occurrences are thought to arise

from misuse or use on traumatized or

abnormal skin [182]

Briggs: because of potential toxicity,

suggests pyrethrins (such as permethrin) as

alternative [183]

USP DI: if used during pregnancy, best not

to exceed recommended dose [184]

Controversial during lactation

USP DI: avoid nursing for 24 hours after

use [184]

Briggs: amount delivered to infant from

lactation may be clinically

insignificant [183]

Malathion A pediculocide B Unlikely Fair TERIS warning: if terato-

genic, risk is likely larger

at greater exposure or ma-

ternal toxicity; feta risk

may rise if maternal red

blood cell cholinesterase

activity is noted

Has not been associated with teratogenicity

Permethrin An animal tumorigen [185]; no evidence of

animal teratogenicity [186]

B Undetermined Very

limited

No indication of high risk

of congenital anomalies

Poorly absorbed [187]

Given its extensive use, minimal adverse

effects reported [188]

During pregnancy, topical form is

recommended as preferred treatment of

scabies and lice [189–191]

Manufacturer: given animal tumorigenicity,

recommends against lactation during

use [185]

USP DI: notes tumorigenic potential,

supporting manufacturer’s view [192]

Briggs: compatible with lactation [191]

AAP has no rating


Table 11

Antiviral agents in pregnancy and lactation

Class Data [Ref.]

FDA

pregnancy

category

TERIS

Risk Data rating

Notes when

applicable

Acyclovir Not teratogenic in animals but causes fetal

death, growth retardation, malformations in

rats at maternotoxic doses [193,194]

B Topical form:

undetermined

Topical form:

limited to fair

—

Has not been associated with adverse fetal

effects during human pregnancy [195]

Systemic form:

unlikely

Systemic form:

fair

Briggs: insufficient data to establish

safety [196]

Briggs: helpful in reducing mortality from

disseminated herpes simplex virus

infections (HSV); however, use in recurring

HSV infections is not as convincing [196]

Not necessary during pregnancy, except

near term or in cases of severe systemic

viral involvement

Manufacturer: use with caution during

lactation [197]

AAP, Briggs: compatible with

lactation [6,196]

Famciclovir No teratogenicity shown in animals. B Unrated — —

Causes benign tumors in rats [198]

Manufacturer: during pregnancy, use only

when potential benefit to patient clearly

exceeds potential risk to fetus [199]

Briggs: given rat tumorigenicity, advises

discontinuation during lactation [198]

Valacyclovir The pro-drug of acyclovir B Unrated — —

Has not been associated with animal

teratogenicity

Manufacturer reports uneventful use during

pregnancy, but recommends only if

potential benefit to patient outweighs

potential risk to infant [200]

Guidelines for use of acyclovir should

be followed

Manufacturer: use with caution during

lactation [200]

AAP: no rating

Briggs: compatible with lactation [196]

leachman & reed184

Physicians may also wish to consult Reproductive

Toxicology Service, which provides a computer-

based software or on-line program available by sub-

scription (see www.reprotox.org). References on the

effects of drugs and physical agents on human

fertility, pregnancy, and fetal development are

updated regularly. No rating system is included.

Finally, the World Health Organization publishes a

book on lactation, available through libraries [96].

TERIS provides information on the relative tera-

togenicity of agents and reports ‘‘permanent abnor-

malit[ies] of structure or function in an organism

exposed during embryonic or fetal life’’ [28]. Com-

prehensive summaries implement a rating system that

includes none, unlikely, minimal, moderate, high, and

undetermined. Qualifying these risks is an evaluation

of data on which these risks have been based: none,

poor, limited, fair, good, and excellent.

http://www.reprotox.org

Table 12

Biologic agents in pregnancy and lactation

Class Data [Ref.]

FDA

pregnancy

category

TERIS

Risk Data rating

Notes when

applicable

Adalimumab No human studies have been conducted B Undetermined None —

No apparent evidence of embryotoxicity,

teratogenicity, or increased pregnancy

loss [201]

A pregnancy registry has been established

Briggs: potential maternal benefits appear to

be great and probably outweigh the

unknown fetal risk; treatment during first

trimester should be discussed with

patient [202]

No data available for use during lactation

Manufacturer: citing potential for adverse

reaction, suggests discontinuation during

lactation [201]

Briggs: probably compatible with

lactation [202]

AAP: unrated

Etanercept No evidence of adverse effects on humans,

but is very new

B Undetermined Very limited —

A pregnancy registry has been established

Manufacturer: recommends discontinuation

of breastfeeding during use given potential

adverse reaction in infants [203]


lactation [204]

Infliximab Has not been studied in animals given

difference of mechanism of action in

humans; has not been studied in humans

B Undetermined None —

Manufacturer has established a

pregnancy registry

Briggs: real risk is unknown, given similar

mechanism of action as thalidomide;

potential for serious maternal reactions in

some patients; limited human data [205]

Manufacturer: advises against

breastfeeding during use [206]


lactation [205]

AAP: unrated


The FDA’s rating system (Table 5), developed out

of a 1996 task force, is the most well known and

followed [97]. Physicians should note that no drugs

listed in this article have been assigned the rating A.

The FDA also provides two lactation drug risk

categories: discontinue and caution. ‘‘Discontinue’’

points out that a ‘‘decision should be made whether to

discontinue nursing or to discontinue the drug, taking

into account the importance of the drug to the

mother.’’ The category ‘‘Caution is advised if the

drug is used during lactation’’ is used if the drug is

absorbed and excreted into human breast milk but

does not have known adverse reactions or tumori-

genic potential.

Most physicians are aware of the FDA pregnancy

categories, but other ratings are also used in the tables

Table 13

Corticosteroids in pregnancy and lactation

Class Data [Ref.]

FDA

pregnancy

category

TERIS

Risk

Data

rating

Notes when

applicable

Corticosteroids,

systemic,

general

Animal studies show use during pregnancy to be

associated with increased risk of cleft palate, placental

insufficiency, spontaneous abortion, and growth

retardation in utero [207,208]

C Unlikely Fair to

good

While therapeutic

doses during

pregnancy are

unlikely to pose

a substantial

teratogenic risk,

data are

insufficient

to claim no risk

USP DI, low dose: no teratogenic effect or serious

problem observed in humans [209]; high dose: use

during human pregnancy is associated with potential

risk of placental insufficiency, decreased birth weight,

or stillbirth [209]

Oral clefts were found to be three times more common

in infants of women treated with oral steroids than in

controls in a prospective study [210]

Low birth weight associated with 10 mg/d doses through-

out pregnancy [211,212]; may be linked to later develop-

ment of hypertension and cardiovascular mortality [213]

To minimize infant exposure, delay nursing 3–4 h

after dose [214]

Use during lactation has been called ‘‘safe’’ [215]

AAP: use is compatible with lactation [6]

Corticosteroids,

topical,

general

Use during pregnancy is not thought to be associated

with significant risk to fetus

C Unlikely Poor

to fair

—

Limited-time use has not been associated with

congenital anomalies, in general

Use of large amounts over extensive parts of the body

during pregnancy may be associated with low birth

weight

Should not be applied to breasts until nursing ceases.

Hypertension is reported in an infant whose mother

applied topical steroids to the nipple [216]

Prednisonea Briggs: poses a small risk of orofacial clefts to

developing fetus [217]

C, Db — — —

Congenital cataracts were reported in an infant of a

mother treated throughout pregnancy [218]

Use of 40–80 mg/d doses for short periods of time has

not increased risk of congenital anomalies, except when

antiphospholipid abnormalities presented a confounding

factor [219]

During lactation: a 5 mg/d systemic dose appears not to

affect blood chemistry or infection rate of nursing

infants [218]

During lactation: if therapy is long-term or requires

doses exceeding 20 mg/d, prednisolone should be

substituted [214]

Prednisolonea Briggs: Poses a small risk of orofacial clefts to

developing fetus [217]

C, Db — — —

To be preferred during lactation to prednisone if therapy

is long-term or requires doses exceeding 20 mg/d [214]

Triamcinolonec Intrauterine growth retardation was reported in an infant

of a mother who used the equivalent of 40 mg/d through

topical application [220]

— — — —

a See also Corticosteroids, systemic, general above.b Briggs: during first trimester [198].c See also Corticosteroids, topical, general above.

leachman & reed186

Table 14

Immunomodulators in pregnancy and lactation

Class Data [Ref.]

FDA

pregnancy

category

TERIS

Risk Data rating

Notes when

applicable

Cyclosporine USP DI: systemic use is not terato-

genic, but embryotoxic, fetotoxic, and

carcinogenic in some animal studies

[221]

C Malformations:

minimal

Malformations:

fair

—

Briggs: studies show use during

pregnancy poses no risk to developing

fetus, but very limited data [222]

Intrauterine

growth

retardation:

small to

moderate

Intrauterine

growth

retardation:

fair

Use during lactation is not recommended by

manufacturers, given risk of nephrotoxicity,

hypertension, and malignancy in infants

[223,224]

AAP recommends against use during

lactation, citing possible immunosup-

pression, unknown effect on growth, or

association with carcinogenesis [6]

Briggs: use during lactation poses

potential toxicity for infant [222]

Imiquimod USP DI: at maternotoxic doses, topical

form has been shown to produce

reduced pup weights and delayed

ossification in rats [225]

C Not listed — —

Not shown to be distributed in human

milk [226]

AAP has no rating

Mycophenolate

mofetil

Not recommended for use during

pregnancy

C Undetermined Limited Not recommended

during pregnancy,

given possibly

substantial

interference with

DNA and RNA

synthesis in fetus

Manufacturer: effective contraceptive

must be used before, during, and six

weeks after use [227]

Manufacturer, Briggs: contraindicated

during lactation [228]

AAP has no listing

Pimecrolimus No problems during pregnancy reported C Unrated — —

Manufacturer: use during lactation is

contradicted [229,230]

AAP, Briggs: no rating

FDA issued Public Health Advisory,

March 2005, citing unknown risk of

lymphoma after topical use

Tacrolimus No problems during pregnancy reported. C Undetermined Limited Neonatal

hyperkalemia

reported in infants

of mothers treated

with oral form

after transplant

Manufacturer: use during lactation is

contraindicated [230]

Briggs: data are limited on human

lactation. Given potential toxicity,

advises against use of oral form [231]

AAP: no rating

FDA issued Public Health Advisory,

March 2005, citing unknown risk of

lymphoma after topical use


Table 15

Miscellaneous drugs in pregnancy and lactation

Class Data [Ref.]

FDA

pregnancy

category

TERIS

Risk

Data

rating

Notes when

applicable

Calcipotriene A vitamin D analog. High oral doses of

vitamin D show skeletal abnormalities in

animal studies; similar findings not

confirmed in human studies [232]

C Undetermined Very

limited

High risk, in

recommended doses,

is unlikely

A pregnancy registry has been established.

Risk of congenital

abnormalities may be

higher in infants of

mothers with

hypervitaminosis D

Topical use shows no fetal toxicity until

maternal toxicity has been approached

No problems identified with use during

lactation. Manufacturer does not

contraindicate such use [233]

Briggs: vitamin D use is compatible with

lactation [232]

Coal tar A known carcinogen and mutagen [234] C Undetermined None High risk is unlikely

Use of shampoo is associated with uptake

of coal tar [235]

No human studies have been conducted.

No information is available on use during

lactation

Precipitated

sulfur

Applied to abraded skin, associated with

fatalities after use in animals and humans in

one report [236]

— — — —

During pregnancy, use of alternatives is

preferable given relative ineffectiveness

No information germane to lactation

Box 1. Pregnancy category X: avoid inpregnancy and lactation

AcitretinEstrogensEtretinateFinasterideFluorouracilFlutamideIsotretinoinMethotrexatea

StanozololTazaroteneThalidomidea

a Both men and women should avoid ifpregnancy is anticipated.

leachman & reed188

that may or may not be entirely consistent with those

listed by the manufacturer. For example, Briggs and

coworkers [98] have modified the rating somewhat,

based on evaluation of human and animal data, route

of administration, and risk of maternal disease among

other distinctions. Revisions of FDA pregnancy

categories may be forthcoming, because the catego-

ries are found to be confusing and sparse with help-

ful data.

Revisions may not always come in the form of

a new category. In 2006, the FDA will implement

its plan to restrict the use of isotretinoin, already a

category X drug, by requiring prescribers and patients

to be registered before they can dispense or take the

drug. In August 2005, the FDA approved that plan,

known as iPLEDGE ‘‘to make sure females do not

become pregnant while taking this medicine. Iso-

tretinoin causes birth defects’’ [61].

The example of isotretinoin marks the impor-

tance of staying up-to-date with pregnancy and

breast-feeding ratings. Advances in knowledge of

Box 2. Drugs with minimal risk to motherand fetus during pregnancy

Analgesics

AcetaminophenAspirin (low-dose; avoid preconception

and third trimester)Codeine (low-dose)Ibuprofen (low-dose; avoid preconcep-

tion and third trimester)Meperidine (low-dose)Oxycodone (low-dose)Propoxyphene (low-dose)

Anesthetics

LidocaineLidocaine with epinephrineLidocaine-prilocaine

Antibacterial agents

Bacitracin (topical)Clindamycin (topical)Erythromycin (except estolate)Erythromycin (topical)Metronidazole (topical)Mupirocin (topical)Neomycin (topical)PenicillinsPolymyxin B (topical)Sulfonamides (except third trimester)Sulfur (topical)Sulfur with resorcinol (topical)

Antifungal agentsa

Butaconazole (topical)Ciclopirox (topical)Clotrimazole (topical; except

first trimester)Econazole (topical; except first trimester)Fluconazole single doseKetoconazole (topical)Miconazole (topical; except

first trimester)Naftifine (topical)Nystatin (oral and topical)Oxiconazole (topical)Sulconazole (topical)Terbinafine (topical)

Antihistaminesb

Cetirizine (except first trimester)CyproheptadineDiphenhydramineFexofenadineHydroxyzine (except first trimester)Loratadine

Antiscabetic and antipediculocidal agents

Crotamiton (topical)Malathion (topical)Permethrin (topical)Precipitated sulfur (topical)

Antiviral agentsc

AcyclovirFamciclovirValacyclovir

Corticosteroids

Oral (avoid high doses first trimester)Topical (avoid high doses long term)

Miscellaneous: topical antiacne products

Benzoyl peroxideClindamycinErythromycin

Miscellaneous: other drugs

Calcipotriene (topical; low doses)

a Avoid vaginal use after mem-brane rupture.

b Avoid last 2 weeks of pregnancy iffetus is premature.

c Restrict use to treatment of severeherpes virus infections.


the effects of drugs on fetuses and nursing infants

are continuous.

Tables 6–15 group drugs by their ratings and are

included for further ease of reference [1–4,6,26,27,

29–31,45,49–51,55,82,84–92,99–236]. Boxes 2

and 3 list drugs of minimal risk to mother and fetus

Box 3. Drugs with minimal risk to motherand infant during lactation

Analgesics

AcetaminophenCodeine (low-dose)Meperidine (low-dose)Morphine (low-dose)Oxycodone (low-dose)Propoxyphene (low-dose)

Anesthetics

LidocaineLidocaine with epinephrineLidocaine-prilocaine

Antibacterial agents

Bacitracin (topical)CephalosporinsErythromycinsErythromycin (topical)PenicillinsSulfur (topical)Sulfur with resorcinol (topical)Tetracycline (topical)

Antifungal agents

Ciclopirox (topical)Clotrimazole (topical)Econazole (topical)Miconazole (topical)Naftifine (topical)Nystatin (oral and topical)Oxiconazole (topical)Sulconazole (topical)Terbinafine (topical; not on nipple)

Antihistamines

LoratadineFexofenadine

Antiviral agents

AcyclovirValacyclovir

Antiscabetic agents

Crotamiton (topical)

Corticosteroids

Oral: use prednisolone; avoid nursingfor 4 hours after use

Topical: avoid use on nipple or areola

Miscellaneous: topical antiacne products

Azelaic acidBenzoyl peroxideRetinoidsAdapaleneTretinoin

Miscellaneous: other drugs

Calcipotriene (topical)

leachman & reed190

during pregnancy and to mother and infant during

lactation, respectively.

Summary of cautions in treating women of

childbearing age

Given the importance of the possible phases of

pregnancy of any woman of childbearing age, the

physician should determine whether the patient is

using contraception, attempting to become pregnant,

is already pregnant, or is lactating before any

dermatologic treatment is recommended. Subtle dis-

tinctions within the three trimesters of pregnancy

must also be considered. In sum:

� If the patient is attempting to avoid conception

through the use of contraceptive drugs or de-

vices, the physician should determine the pos-

sible interaction of dermatologic drugs and the

contraception used before prescribing derma-

tologic therapy. Contraceptive failure presents a

risk to the patient.� If the patient is currently not pregnant but is

trying to conceive, she should be asked to

disclose her pregnancy as soon as possible after

conception because of possible risk to herself or

her fetus. The physician also should educate the


patient about the possible risks of drug therapies

used at the time of conception.� If a woman is not pregnant and is taking a

medication that places her at high risk for

problems during early pregnancy (eg, metho-

trexate, isotretinoin, thalidomide), she should be

extensively counseled about the risk to her and

her fetus. In addition, she should have regular

pregnancy testing before and during her treat-

ment course and use an effective form of birth

control throughout the treatment.� If a woman is pregnant, her physician should

determine her estimated date of conception and

current trimester of pregnancy. Risks of drugs

vary depending on the trimester of pregnancy.� If the patient is pregnant and has urgent need of

a medication that places her or her fetus at risk,

her physician should review her actual risk from

the previously mentioned sources, especially

TERIS and Drugs in Pregnancy and Lactation

[94]. It is recommended that the physician

document the discussion of risk with the patient.� If a patient is very near term, the physician

should take careful note of those dermatologic

drugs that are contraindicated in the last 2 weeks

of pregnancy. Table 2 provides a prime example

on antihistamines.� When an optional drug poses minimal risk, dis-

cussion of the options with the patient and her

obstetrician, pediatrician, and primary care phy-

sicians is advised. The dermatologist should

anticipate that the patient’s other health care

providers may be inclined toward or against

the use of certain drugs during pregnancy

or lactation.� If a drug therapy is optional and the manufac-

turer publishes a contraindication of use during

pregnancy or breast-feeding, the drug should

be prescribed only under exceptional clinical

circumstances: if the patient’s overall health

is at significant risk, and after discussing the

risks and benefits with the patient, the father,

and their obstetrician or pediatrician. Docu-

mentation of the risk-benefit conversation is

strongly advised.� Because breast-feeding affects the proper choice

of drug therapy, the physician treating a preg-

nant patient should determine if she plans to

nurse. If a female patient is not pregnant, the

physician should ask if she is nursing. Drugs of

minimal risk in pregnancy may present greater

risk during lactation, whereas drugs that are

contraindicated during pregnancy may be safe

during lactation. Two choices present them-

selves in treating a nursing patient. A drug treat-

ment can be avoided or suspended until after

nursing ceases or nursing can be avoided or sus-

pending during treatment.

Controversy among sources over the use of drugs

during lactation may complicate the physician’s

choice of treatment. The best sources for information

on risk during lactation include Drugs in Pregnancy

and Lactation [94], the AAP [6], and the World

Health Organization [96].

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The Use of Dermatologic Drugs in Pregnancy and Lactation

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