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Pregnancy, breast-feeding and drugs used in dentistry

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CLINICAL PRACTICE

Pregnancy, breast-feeding and drugs used

in dentistry
Mark Donaldson, BSP, PharmD, FASHP, FACHE; Jason H. Goodchild, DMD

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edication use during preg-

M nancy is common; two of

every three women take
prescription medications
during pregnancy.1 Despite advances
in the study of birth defects related
to exposures during pregnancy (tera-
tology), medication use during preg-
nancy still causes anxiety and mis-
understanding among both members
of the public and health care profes-
sionals. This may result in a wom-
an’s unknowingly taking a medica-
tion that may harm the fetus or
cause a birth defect or in her discon-
tinuing the use of medications neces-
sary for treating conditions such as
diabetes, asthma or influenza. For
the health care professional, the
challenge is to know which drugs
may be safe for the pregnant patient
and which medications to avoid.
Although drug use is an uncom-
mon cause of birth defects, approxi-
mately 120,000 children (3 to 5 per-
cent of live births) are born with
birth defects each year in the United
States.2 Because of the obvious eth-
ical and moral limitations of
designing double-masked, prospec-
tive studies to ascertain the risk of
medications’ causing birth defects or
malformations, investigators typi-
cally have used cohort studies to
examine fetal risk after maternal use
Dr. Donaldson is the director of pharmacy services, Kalispell Regional Medical Center, Kalispell, Mont.; a clinical professor, Skaggs School of Pharmacy,
University of Montana, Missoula; and a clinical assistant professor, School of Dentistry, Oregon Health & Sciences University, Portland. Address reprints to
Dr. Donaldson at 310 Sunnyview Lane, Kalispell, Mont. 59901, mdonaldson@krmc.org.
Dr. Goodchild is a clinical associate professor, Department of Oral Medicine, School of Dental Medicine, University of Pennsylvania, Philadelphia; and a
private practitioner in Havertown, Pa.
AB STRACT
Background and Overview. Despite advances in the study
of birth defects related to drug exposures during pregnancy, med-
ication use during pregnancy still causes anxiety and misunder-
standing among both members of the public and health care profes-
sionals. This may result in a woman’s unknowingly taking a
medication that may harm the fetus or cause a birth defect or dis-
continuing medications necessary for treating chronic conditions.
Using medications while breast-feeding also represents a challenge
for patients and prescribers. Many mothers are told they must stop
breast-feeding or “pump and discard” their breast milk if they are
taking certain medications; however, in many cases, this advice—
based on what may be limited education on the part of the health
care provider about breast-feeding and medication use—may be
incorrect. The authors review the current evidence regarding drugs
that may be safe for pregnant or breast-feeding patients and med-
ications that such patients should avoid.
Conclusions. When considering prescribing in pregnancy, the
dentist must weigh the risk to the fetus versus the benefit to the
mother, and the appropriate conclusion should reflect current evi-
dence. In some cases medication dosing should be avoided or
altered; however, there are times when it is unnecessary to stop the
use of medications. Breast-feeding also represents a clinical chal-
lenge, the risks and benefits of which need to be understood by both
the patient and practitioner before any medication is administered.
Practice Implications. Dentists should be familiar with the
risks and benefits for pregnant or breast-feeding patients posed by
five types of medications: analgesics and anti-inflammatories,
antibiotics, local anesthetics, sedatives and emergency medications.
Key Words. Pregnancy; pregnancy complications; risk assess-
ment; medications; lactation; fetotoxicity; teratology.
JADA 2012;143(8):858-871.

858 JADA 143(8) http://jada.ada.org August 2012

Copyright © 2012 American Dental Association. All rights reserved.

of medication.3-5 The majority of birth defects
have an unknown cause. To our knowledge and
according to our research, no current statistics
exist describing the risk of birth defects caused
by maternal use of medication; however, authors
of a 1973 article estimated that 2 to 3 percent of
birth defects were thought to be caused by med-
ications used during pregnancy.6
Medication use during breast-feeding also rep-
resents a challenge for patients and prescribers.
Many new mothers are told they must discon-
tinue breast-feeding or must “pump and discard”
their breast milk if they are taking certain med-
ications; however, in many cases, this advice—
based on what may be limited education on the
part of the health care provider about breast-
feeding and medication use—may be incorrect.
Pregnant patients can receive most dental
treatment safely.7 The dental practitioner pre-
scribes a relatively small group of medications,
which somewhat simplifies the issue of medica-
tion use in patients who are either pregnant,
trying to conceive or breast-feeding. Primarily,
dentists should be familiar with the risks and
benefits of five types of medications: analgesics
and anti-inflammatories, antibiotics, local anes-
thetics, sedatives and emergency medications.
Our purpose in this article is to provide, by
using data collected by the U.S. Food and Drug
Administration (FDA)8 and other sources, an
organized reference for information about the use
of prescription medication in the dental patient
who is pregnant or breast-feeding. Health care
professionals who are prepared with evidence-
based information about the safety of medication
use during pregnancy and breast-feeding can
advise their patients regarding optimal medica-
tion therapy, thereby helping to ensure healthy
outcomes for both mother and baby. We based
this literature review on searches of knowledge-
based resources without any restrictions on dates
of publication: MEDLINE, PubMed, Embase, and
the Cochrane Database of Systematic Reviews.
The search terms were “pregnant” and “den-
tistry”; “lactation” and “dentistry”; “risk manage-
ment”; “teratology”; and “fetotoxicity.” In addition,
we also evaluated journals, Web sites, textbooks,
studies, reports, conference proceedings, con-
sensus statements and abstracts published in
English. Our intention was to be as comprehen-
sive as possible, but we focused specifically on the
last 50 years because much of the newer informa-
tion continues to reference older, original studies.
THE PREGNANT DENTAL PATIENT
The pregnant dental patient represents two sig-
nificant challenges to the dental professional.
Copyright © 2012 American Dental Association. All rights reserved.
CLINICAL PRACTICE
First, although most dental procedures are elec-
tive and can be postponed until after the preg-
nancy is over, dental treatment for a pregnant
woman who has oral pain, advanced disease or
infection should not be delayed. Second, not all
women of childbearing age know that they may
be pregnant, and when selecting and pre-
scribing a medication for any woman of child-
bearing age, the clinician always should con-
sider the possibility of her conceiving while she
still is receiving the medication.
The rate of unintended pregnancy fell nearly
20 percent between the early 1980s and the mid-
1990s,9 but it has remained relatively unchanged
since.10 The initial decline probably was a result
of better public education, higher prevalence of
contraceptive use and use of more effective con-
traceptive methods; nevertheless, authors of one
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study estimated that 48 percent of women aged
15 to 44 years have had at least one unplanned
pregnancy sometime in their lives.9 Therefore,
the clinician must consider the potential adverse
effects on a fetus whenever prescribing medica-
tion for women of childbearing age. In addition to
routinely updating every patient’s medical and
pharmacological history, one simple interview
technique involving three questions for all female
patients may aid greatly in risk mitigation: Are
you pregnant? Do you know if you are pregnant?
Are you trying to get pregnant?
Teratogenic drugs are medications that may
be associated with the development of structural
abnormalities in a developing fetus (such as cleft
lip, cleft palate and phycomelia). The greatest
teratogenic risk to the fetus is from three to
eight weeks after conception (five to 10 weeks’
gestation, with week one beginning on the first
day of the last menstrual period).11 Placental
transport of maternal substrates to the fetus and
of substances from the fetus to the mother is
established at about the fifth week of embryonic
life.12 Therefore, abruptly ceasing intake of a
drug at week 10 because of concerns about ter-
atogenicity usually does not reduce the risk of
malformation substantially. Beyond teratogen-
esis, fetotoxicity can occur at any time between
the late first trimester and birth and may cause
a variety of effects. An example is the use of non-
steroidal anti-inflammatory drugs (NSAIDs),
which may be associated with fetal renal dys-
ABBREVIATION KEY. AAP: American Academy of
Pediatrics. CDC: Centers for Disease Control and
Prevention. FDA: Food and Drug Administration.
G6PD: Glucose-6-phosphate dehydrogenase.
NSAIDs: Nonsteroidal anti-inflammatory drugs.
OTC: Over the counter. PR: Pregnancy risk.
JADA 143(8) http://jada.ada.org August 2012 859
CLINICAL PRACTICE

TABLE 1 during the pregnancy

U.S. Food and Drug Administration pregnancy risk depending on the dis-
ease activity and the
factor definitions.* gestation.17 For
CATEGORY DEFINITION example, a woman
A The results of controlled studies in women fail to demonstrate a risk to the fetus
with a flare-up of a
in the first trimester (and there is no evidence of risk in later trimesters), and the severe inflammatory
possibility of fetal harm appears remote bowel disease may be
B Either the results of animal reproduction studies have not demonstrated a fetal a candidate for bio-
risk but there are no controlled studies in pregnant women logical therapy in the
OR
the results of animal reproduction studies have shown an adverse effect (other first trimester (as
than a decrease in fertility) that was not confirmed in controlled studies in several biological
women in the first trimester and there is no evidence of risk in later trimesters
agents have been
C Either the results of studies in animals have revealed adverse effects (teratogenic, shown not to cross
embryocidal or other) on the fetus and there are no controlled studies in women
OR the placenta until
results of studies in women and animals are not available; drug should be given well into the second
only if the potential benefit justifies the potential risk to the fetus trimester18); however,
D There is positive evidence of human fetal risk, but the benefits of use in pregnant in the third trimester,

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women may be acceptable despite the risk (for example, if the drug is needed in
a life-threatening situation or for a serious disease for which safer drugs cannot
it may be reasonable
be used or are ineffective) to try high-dose
X Results of studies in animals or humans have demonstrated fetal abnormalities or steroids first because
evidence of fetal risk based on human experience, or both, and the risk of the use they may be consid-
of the drug in pregnant women clearly outweighs any possible benefit; use of the ered safer.19
drug is contraindicated in women who are or may become pregnant
8,20,21
To determine the
* Sources: U.S. Food and Drug Administration.
risks associated with
the use of drugs in
function in the second and third trimester and pregnancy, the FDA traditionally has classified
premature closure of the ductus arteriosus in the drugs on the basis of the level of risk they pose
third trimester.13,14 Potential effects of drugs on to the fetus8,20,21 (Table 18,20,21). Accordingly, drugs
cognitive function by interference with brain in categories A and B are considered safe for
development are less obvious and harder to use, whereas drugs in category C may be used
detect than are structural anomalies or only if the benefits outweigh the risks. Use of
malformations. drugs in category D should be avoided except in
Any drug or chemical substance administered certain exceptional circumstances, and use of
to the mother can cross the placenta to some category X drugs in pregnant women is strictly
extent unless it is destroyed or altered during prohibited.
passage, or unless its molecular size and low In May 2008, the FDA proposed major revi-
lipid solubility limit transplacental transfer.15 sions to prescription drug labeling to inform pre-
Substances of low molecular weight (< 600 dal- scribers more completely about the use of medi-
tons) diffuse freely across the placenta, driven cines during pregnancy and breast-feeding.21 The
primarily by the concentration gradient.16 Some proposed changes to medication labeling would
examples of these medications include aceta- give health care providers better information for
minophen, aspirin and most glucocorticoids. It making prescribing decisions and for counseling
is important to note that almost every sub- women who are pregnant, breast-feeding or of
stance used for therapeutic purposes can and childbearing age. The FDA proposed that both the
does pass from the mother to the fetus; in other pregnancy and lactation subsections of provider
words, the concept of a “placental barrier” is a labeling include a risk summary, listing clinical
misnomer. Of greater importance is whether the considerations to support patient care decisions
rate and extent of transfer are sufficient to and counseling and containing a data section that
result in significant concentrations within includes more detailed information. The proposed
the fetus to cause either teratogenicity or regulations would eliminate the pregnancy cat-
fetotoxicity. egories A, B, C, D and X owing to limitations in
The aim when prescribing medication to a their ability to convey risk and benefit accurately
pregnant patient is to balance the risks of the and consistently. Information about the use of
drug’s potential adverse effects (usually on the medicines during labor and delivery would be-
fetus) with the benefit (usually to the mother) of come a part of the pregnancy subsection. Oppo-
treating the disease. This balance may change nents of this proposal suggest that without stan-

860 JADA 143(8) http://jada.ada.org August 2012

Copyright © 2012 American Dental Association. All rights reserved.

dardized labeling requirements, the private
sector could conduct narrative discussions about
risk and develop a wide array of schema and
rules to support decisions about pregnancy risk
for patient medication use that are not clinically
relevant. Such discussions could lead to differing
interpretations of risk assessment and could com-
promise patient safety. As of June 2012, the Final
Rule is in the writing and clearance process and
has yet to be approved officially.
Box 1 highlights key clinical considerations
for clinicians prescribing medications for preg-
nant patients.
THE BREAST-FEEDING DENTAL PATIENT
In 2010, the Centers for Disease Control and Pre-
vention (CDC) released data regarding the inci-
dence of breast-feeding among U.S. children born
between 2000 and 2008.22 The survey found that
breast-feeding percentages in the early post-
partum period, at six months after delivery and
at 12 months after delivery were 81.9, 60.6 and
34.1 percent, respectively. These relatively high
percentages may be due in part to the American
Academy of Pediatrics’12 (p xvii) (AAP’s) position
paper on this subject, which emphasized breast-
feeding as the best nutritional mode for infants
for the first six months of life. The high rates of
breast-feeding, together with growing concern
about health needs on the part of parents, may
lead to more patients’ questioning physicians,
pharmacists and dentists about the safety and
potential toxicity of drugs and chemicals that
may be excreted in breast milk.
To date, many of the studies involving milk
secretion and synthesis have been carried out in
animals.23 The challenge in studying human lac-
tation by using histologic techniques and the
administration of radioactive isotopes is obvious.
Unfortunately, there are considerable differences
in the composition of milk in different species,
and some of these differences in composition
would bring about changes in drug elimination.
Of great importance in this regard are the differ-
ences in the pH of human milk (usually > 7.0)
and the pH of cow’s milk (usually > 6.8), in
which drug excretion has been studied more
extensively in the bovine model.12 In general, the
factors that increase the transfer of medications
into breast milk are low molecular weight, low
protein binding (which leads to an increased
amount of free drug), high lipid solubility and
existing as a weak base.24
Many reviews include tables of the concentra-
tion of drugs in breast milk and, often, of the
milk-to-plasma ratio.25-27 The values from which
the data in these tables are derived consist of a
Copyright © 2012 American Dental Association. All rights reserved.
CLINICAL PRACTICE
BOX 1
Clinical considerations
regarding medication use
in patients who are pregnant.
Use medication only if the expected benefits (usually to
the mother) are greater than the potential risks (usually
to the fetus)
Try to avoid prescribing medication during the patient’s
first trimester of pregnancy
Prescribe drugs that have been used extensively by
pregnant women, not new drugs that may yet be
untested in pregnant patients
Prescribe the minimum dose required to obtain the
desired effect
Recognize that the absence of data does not imply safety
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single measurement of the drug concentration,
and important information—such as the ma-
ternal dose, the frequency of dose, the time from
drug administration to sampling, the frequency
of nursing and the length of lactation—is not
provided. The clinical significance of these con-
centration tables is limited, because the mere
knowledge that the drug is present in the milk
does not equate to advice for the prescriber. With
little information about the amount of the med-
ication that the infant actually absorbs from the
milk, we, therefore, have no way of determining
the possible pharmacological effects on the
infant. In fact, we found that much of the infor-
mation in these tables was gathered decades
ago, when analytic methodology was not as sen-
sitive as it is today.26-30
For most drugs, the infant is exposed to a
much higher concentration during pregnancy
than during lactation. Therefore, if a drug is con-
sidered acceptable for use during pregnancy, it
usually is reasonable to continue its use during
breast-feeding.31 However, there are exceptions,
and the most important factors to consider are
the concentration of the drug in the infant’s
blood and the effects that this might have. Small
drug molecules enter breast milk more easily
than do large molecules (for example, heparin, a
large molecule, is not excreted in breast milk).
The half-life of some drugs in the neonatal circu-
lation also may be longer than that in the
mother, because an infant’s liver metabolism is
immature. This may lead to accumulation of the
drug in the infant; this phenomenon particularly
applies to morphine, lamotrigine, phenobarbital,
some benzodiazepines and aspirin.12,32-34 The
pump-and-discard strategy can be effective for
women taking some medications with a short
half-life.35-37 This is best demonstrated with the
JADA 143(8) http://jada.ada.org August 2012 861
CLINICAL PRACTICE
BOX 2
Clinical considerations
regarding medication use in
patients who are breast-feeding.
Advise the patient to minimize the breast-fed child’s
exposure to drugs the mother is receiving, such as by
timing feedings or pumping and discarding milk
Recognize potential drug effects in the child and make
recommendations to the patient about monitoring or
responding to these effects
Consider adjusting dosage during lactation
Understand the effects of the drug on milk production and
explain these effects to the patient clearly
Ascertain whether the drug is present in human milk (and
if so, how much)
Realize the effects of the drug on the breast-fed child and
explain these effects to the patient clearly
enterally administered sedative triazolam. The
lactating mother who is to receive triazolam is
counseled to pump and save a surplus supply of
her breast milk before the dental appointment.
She receives triazolam before the dental ap-
pointment to help ameliorate her anxiety, and
for the eight to 10 hours after the dental ap-
pointment (that is, four half-lives of the drug),
she will pump and discard the milk, feeding her
baby with the milk she had pumped and saved
from the previous day. After the four half-lives
have passed, she then can return to her regular
breast-feeding schedule. It takes approximately
four half-lives for more than 90 percent of most
medications to be eliminated from the body.38
Box 2 summarizes and highlights key clinical
considerations regarding medications and
breast-feeding.
DRUGS COMMONLY USED IN DENTISTRY
As previously mentioned, drugs should be pre-
scribed in pregnancy only if the expected benefit
to the mother is thought to be greater than the
risk to the fetus, and use of all drugs should be
avoided if possible during the first trimester. Cli-
nicians should prescribe drugs that have been
used extensively in pregnant patients and that
appear to be usually safe rather than prescribe
new or untried drugs, and they should prescribe
the smallest effective dose for the shortest clini-
cally effective length of time. Although only a
few drugs have been shown conclusively to be
teratogenic in humans, in early pregnancy, no
drug is safe beyond all doubt.
Medications that commonly are used in den-
tistry typically fall into five drug classes: anal-
gesics and anti-inflammatories, antibiotics, local
anesthetics, sedatives and emergency medica-
862 JADA 143(8) http://jada.ada.org August 2012
Copyright © 2012 American Dental Association. All rights reserved.
tions. There may be some additional miscella-
neous medications such as antiseptics (such as
chlorhexidine), fluoride supplements or drugs to
treat xerostomia (such as pilocarpine); however,
it is unlikely that drugs in these last three cat-
egories absolutely would need to be used in a
pregnant or breast-feeding patient, and it is
likely that their use could be delayed without
harm to the patient. Chlorhexidine and fluoride
supplements have been shown in pregnant and
postpartum mothers to reduce caries risk and
bacterial transmission between mother and
child. Although these studies have focused pri-
marily on factors other than teratogenesis, their
investigators have not reported any harm to the
child.39,40 Theoretically, prenatal fluoride supple-
mentation could impart caries protection to the
unborn child; however, it has been shown that it
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provides no additional benefit.41 In light of insuf-
ficient supporting evidence obviating fetal tox-
icity, prenatal fluoride supplementation cannot
be recommended. In addition, the American
Academy of Pediatric Dentistry42,43 does not sup-
port the use of prenatal fluoride supplementation
as a benefit that outweighs potential risk. Fluo-
ride has a FDA pregnancy risk factor rating of C.
Within the emergency medications section,
we will consider the seven drugs that make up
the minimum emergency kit,44 including the two
reversal agents, naloxone and flumazenil.
Table 2 summarizes key clinical considera-
tions for the medications typically used in den-
tistry; however, the absence of a drug from the
list should not imply its safety in pregnant or
breast-feeding patients.
Analgesics and anti-inflammatories.
Many analgesics are available over the counter
(OTC)—that is, without a prescription—and can
be purchased at many retail outlets besides phar-
macies. As a result of this easy access, the wide-
ranging effects of analgesics often are forgotten
by patients and prescribers alike and not put into
the context of being potentially dangerous during
pregnancy or breast-feeding. A review of human
studies by Burdan and Bełzek45 focusing on the
ingestion of ibuprofen during pregnancy found
that this drug caused embryonic implantation
disturbances, inhibition of parturition and con-
traction of the ductus arteriosis leading to ma-
ternal pulmonary hypertension. Gastroschisis is
a congenital malformation, often related to
ibuprofen use, in which fetal organs develop out-
side the abdominal wall.46 Other drug-related
cases of gastroschisis have been linked to ma-
ternal use of other NSAIDs, including aspirin
and the decongestants pseudoephedrine and
phenylpropanolamine.46 The glucocorticoids, such
 CLINICAL PRACTICE

TABLE 2

Key medication considerations during pregnancy and breast-feeding.

AGENT FDA PR* SAFE DURING SAFE DURING
CATEGORY PREGNANCY? BREAST-FEEDING?
Analgesics and Anti-inflammatories†
Acetaminophen B Yes Yes
Aspirin C/D Avoid Avoid
Codeine C Use with caution Yes
Glucocorticoids (dexamethasone, prednisone) C Avoid‡ Yes
Hydrocodone C Use with caution Use with caution
Ibuprofen§ C/D Avoid use in third trimester Yes
Oxycodone B Use with caution Use with caution
Antibiotics¶#
Amoxicillin B Yes Yes
Azithromycin B Yes Yes
Cephalexin B Yes Yes
Chlorhexidine (topical) B Yes Yes
Clarithromycin C Use with caution Use with caution

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Clindamycin B Yes Yes
Clotrimazole (topical) B Yes Yes
Doxycycline D Avoid Avoid
Erythromycin B Yes Use with caution
Fluconazole C/D Yes (single-dose regimens) Yes
Metronidazole B Yes Avoid; may give breast
milk an unpleasant taste
Nystatin C Yes Yes
Penicillin B Yes Yes
Terconazole (topical) B Yes Yes
Tetracycline D Avoid Avoid
Local Anesthetics
Articaine C Use with caution Use with caution
Bupivacaine C Use with caution Yes
Lidocaine (with or without epinephrine) B Yes Yes
Mepivacaine (with or without levonordefrin) C Use with caution Yes
Prilocaine B Yes Yes
Benzocaine (topical) C Use with caution Use with caution
Dyclonine (topical) C Yes Yes
Lidocaine (topical) B Yes Yes
Tetracaine (topical) C Use with caution Use with caution
Sedatives
Benzodiazepines D/X Avoid Avoid
Zaleplon C Use with caution Use with caution
Zolpidem C Use with caution Yes
Emergency Medications
Albuterol C Steroid and β2-agonist inhalers Yes
are safe
Diphenhydramine B Yes Avoid
Epinephrine C Use with caution Yes
Flumazenil C Use with caution Use with caution
Naloxone C Use with caution Use with caution
Nitroglycerin C Use with caution Use with caution
* FDA PR: U.S. Food and Drug Administration Pregnancy Risk. See Table 1 for FDA PR category definitions.
† In the case of combination products (such as oxycodone with acetaminophen), the safety with respect to either pregnancy or breast-feeding
is dependent on the highest-risk moiety. In the example of oxycodone with acetaminophen, the combination of these two drugs should be
used with caution, because the oxycodone moiety carries a higher risk than the acetaminophen moiety.
‡ Oral steroids should not be withheld from patients with acute severe asthma.
§ Ibuprofen is representative of all nonsteroidal anti-inflammatory drugs. In breast-feeding patients, avoid cyclooxygenase selective
inhibitors such as celecoxib, as few data regarding their safe use in this population are available, and avoid doses of aspirin higher than
100 milligrams because of risk of platelet dysfunction and Reye syndrome.
¶ Antibiotic use during pregnancy: The patient should receive the full adult dose and for the usual length of treatment. Serious infections
should be treated aggressively. Penicillins and cephalosporins are considered safe. Use higher-dose regimens (such as cephalexin 500 mg
three times per day rather than 250 mg three times per day), as they are cleared from the system more quickly because of the increase
in glomerular filtration rate in pregnancy.
# Antibiotic use during breast-feeding: These agents may cause altered bowel flora and, thus, diarrhea in the baby. If the infant develops
a fever, the clinician should take into account maternal antibiotic treatment.

JADA 143(8) http://jada.ada.org August 2012 863

Copyright © 2012 American Dental Association. All rights reserved.
CLINICAL PRACTICE
as prednisone and dexamethasone, have been
associated with oral clefts when administered
during the first trimester of pregnancy.47,48 For
these reasons, the abovementioned medications
all are listed as pregnancy risk factor C or D by
the FDA. The AAP,49 however, did report that use
of these medications may be safe during breast-
feeding—with the exception of aspirin, of which
daily doses of more than 100 milligrams should
be avoided because of the associated risk of
platelet dysfunction and Reye syndrome.
On the basis of the results of three large-scale
epidemiologic studies, the safest analgesic in a
pregnant patient is considered to be acetamino-
phen (also known as paracetamol).46,50,51 The
AAP49 also considers acetaminophen to be com-
patible with breast-feeding. Although low concen-
trations of acetaminophen are excreted into
breast milk and can be detected in the urine of
nursing infants, adverse reactions generally have
not been observed; however, Matheson and col-
leagues52 reported that one breast-fed infant
developed a rash as a result of acetaminophen
exposure.
Narcotics such as codeine, hydrocodone and
oxycodone generally are not recommended as
first-line drugs to treat dental pain, as they lack
anti-inflammatory activity.53,54 If a practitioner
chooses to prescribe one of these agents regard-
less, codeine is considered the safest in regard
to breast-feeding according to the AAP,49 where-
as hydrocodone and oxycodone carry a higher
risk of causing sedation and respiratory depres-
sion in the infant than does codeine23; symptoms
of opioid withdrawal also may occur after the
cessation of breast-feeding.55,56 Of these three
drugs, oxycodone may be the safest; it is listed
as pregnancy risk factor B, and codeine and
hydrocodone are listed as pregnancy risk factor
C. However, the clinician must exercise caution
if prescribing these drugs for prolonged periods
or in high doses. In most cases, the risk to the
infant is minimal, thus making it unnecessary
for a mother receiving an opioid analgesic to dis-
card breast milk.23
Antibiotics. Some antibiotics can cross the
placental membrane and be deposited in the
embryo’s bones and teeth at sites of active calci-
fication. All of the tetracyclines demonstrate
this class effect: as little as 1 gram per day of
tetracycline hydrochloride administered during
the third trimester of pregnancy can produce
yellow staining of both primary and secondary
teeth.57 Doxycycline also has been implicated in
tooth staining.58 Each of these medications is
listed as pregnancy risk factor D by the FDA.
All tetracyclines, including doxycycline, are
864 JADA 143(8) http://jada.ada.org August 2012
Copyright © 2012 American Dental Association. All rights reserved.
excreted in breast milk and, therefore, breast-
feeding is not recommended by the manufac-
turer.59 The AAP49 considers all of these agents
to be compatible with breast-feeding, however.
Doxycycline is less bound to the calcium in
breast milk, which may lead to greater absorp-
tion compared with other tetracyclines. Only
minimal amounts of doxycycline are excreted in
human milk, and the relative amount of tooth
staining has been reported to be lower when
compared with other tetracycline analogs.
On the basis of information from the results
of animal studies, the progenitor manufacturer
of clarithromycin has stated that this antibiotic
should not be used in pregnant women except in
clinical circumstances in which no alternative
therapy is appropriate. Clarithromycin is listed
as pregnancy risk factor C by the FDA and
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although it is not known if clarithromycin is
excreted in human breast milk, the manufac-
turer recommends that caution be exercised
when administering clarithromycin to breast-
feeding women.60 Other macrolides such as
erythromycin and azithromycin are considered
compatible with breast-feeding.61,62
The FDA lists all of the other antibiotics com-
monly used in dentistry—amoxicillin, azith-
romycin, cephalexin, clindamycin, erythro-
mycin, metronidazole and penicillin—as
pregnancy risk factor B. The AAP49 considers all
of these agents to be compatible with breast-
feeding with the exception of metronidazole,
which is considered to be an in vitro mutagen
(meaning that the clinician should suggest that
the patient discontinue breast-feeding for 12 to
24 hours to allow excretion after receiving the
single-dose therapy). Erythromycin also should
be used with caution, as this drug is concen-
trated in human milk, and there are docu-
mented cases of pyloric stenosis being induced
in the breast-fed newborn.63,64
Although antifungal agents are not pre-
scribed commonly by dentists, the appearance of
oral thrush may at times necessitate the use of
these drugs. In the case of oral thrush, oral nys-
tatin (FDA pregnancy risk factor C) is the safest
agent to use both in pregnant patients and in
patients who are breast-feeding, because ab-
sorption after oral use is poor, greatly reducing
the risk to the fetus or the breast-fed newborn.65
The other common indication for antifungals is
for the female dental patient who develops a
vaginal yeast infection secondary to one of the
previously listed antibiotic treatments. Vaginal
candidiasis (moniliasis or thrush) is a common
and frequently distressing infection for many
women, and it is even more common in preg-

nancy.66 The Cochrane Pregnancy and Child-
birth Group Trials Register has reviewed the
Cochrane Central Register of Controlled Trials
and concluded that topical treatments with
either terconazole or clotrimazole not only are
preferred in pregnant women, given the
decreased systemic absorption, but also appear
to be more effective than oral therapies such as
nystatin for treating symptomatic vaginal can-
didiasis during pregnancy.67 Patients may self-
medicate, because many of these preparations
are available OTC. However, the Cochrane
Review on this topic suggests that pregnant
women may require a longer treatment than the
shorter courses more commonly used in women
who are not pregnant; longer courses (seven
days) cured more than 90 percent of women,
whereas standard (four-day) courses cured only
about one-half the affected women.67 Newer oral
agents such as fluconazole provide for equally
efficacious, short-course treatment (from a
single 150-mg dose up to a once-daily, three-day
course) and may be preferred for compliance
reasons. Fluconazole is listed as pregnancy risk
factor C by the FDA for the single-dose vaginal
candidiasis regimen and risk factor D for all
other indications. Regardless, the investigators
in a 2008 trial in Denmark who examined the
maternal use of fluconazole and risk of congen-
ital malformations found no overall increased
risk of congenital malformations after fetal
exposure to short-course treatment with flu-
conazole in early pregnancy.68 Fluconazole is
considered safe in regard to breast-feeding,
according to the AAP.49
Local anesthetics. All local anesthetics
used in dentistry can cross the placental barrier,
primarily through passive diffusion. In general,
there are no contraindications to the careful use
of lidocaine with epinephrine or prilocaine in
pregnant patients (both drugs are listed by the
FDA as pregnancy risk factor B), and both are
considered compatible with breast-feeding
according to the AAP.49 Even in doses exceeding
the maximum allowed in humans, both lido-
caine and prilocaine showed no evidence of fetal
harm.69-73
Authors of articles have listed fetal brady-
cardia as a possible complication for bupiva-
caine and mepivacaine; in addition, bupivacaine
has shown to be embryocidal in rabbits at five
times the maximum recommended daily dose
and can cause decreased survival in newborn
rats at nine times the maximum recommended
daily dose.69,70 Owing to the chance of increased
free-drug concentrations in pregnant women,
Suresh and Radfar72 recommended avoiding the
Copyright © 2012 American Dental Association. All rights reserved.
CLINICAL PRACTICE
use of long-acting local anesthetics such as bupi-
vacaine in these women to minimize the risk of
fetal exposure and toxicity.
Unlike lidocaine and prilocaine, the last three
commonly used local anesthetics—articaine,
bupivacaine and mepivacaine—all are listed by
the FDA as pregnancy risk factor C. Only arti-
caine is not considered compatible with breast-
feeding according to the AAP.49
Topical anesthetics commonly used in den-
tistry include benzocaine, dyclonine, lidocaine
and tetracaine. Of these, lidocaine preparations
are listed by the FDA as pregnancy risk factor
B; the remainder are listed by the FDA as preg-
nancy risk factor C. Local and topical anes-
thetics have been associated with a rare, but
serious potential health concern for both mother
and fetus: a condition called methemoglo-
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binemia. It is caused by the conversion of the
iron molecule in hemoglobin from the ferrous to
the ferric state, which results in an inability of
the hemoglobin molecule to transport oxygen.
Risk factors for developing acquired methemo-
globinemia include the use of oxidative drugs,
patients with glucose-6-phosphate dehydroge-
nase (G6PD) deficiency and use of local anes-
thetics.74-78 Practitioners should use benzocaine
and tetracaine preparations (for example, both
sprays and gels) with caution in pregnant
patients, as these medications have been impli-
cated in acquired methemoglobinemia and pos-
sible hypoxemia in both mother and fetus.72,74
For the same reasons, the clinician should be
cautious in using the injectable local anesthetic
prilocaine. The use of benzocaine, tetracaine
and prilocaine should be avoided altogether in
patients who have a history of either congenital
or acquired methemoglobinemia.
In a review of case reports published in 2000
or later, Guay79 found that benzocaine (in 79
percent of cases) and prilocaine (in 12 percent of
cases) were the local anesthetics most com-
monly associated with acute methemoglo-
binemia episodes. Twelve episodes of methemo-
globinemia were associated with the use of
lidocaine; however, seven of these cases involved
the use of another concomitantly administered
oxidative drug (such as nitrates, trimethoprim-
sulfamethoxazole, dapsone, phenazopyridine or
phenacetin). Because of the unpredictability of
recognizing which patients may develop methe-
moglobinemia after even a single exposure to
benzocaine, it was Guay’s opinion that benzo-
caine topical anesthetic should not be used. To
prevent methemoglobinemia, Guay79 also recom-
mended that the use of prilocaine be avoided in
pregnant women, patients receiving other oxida-
JADA 143(8) http://jada.ada.org August 2012 865
CLINICAL PRACTICE
tive drugs and patients with G6PD deficiency.
Moore and Braatvedt80 reported a rare case of
acquired methemoglobinemia during pregnancy
in which the mother experienced high levels of
methemoglobin; fortunately, the fetus showed
no signs of distress or growth retardation.
The use of lidocaine with epinephrine to
achieve profound anesthesia in pregnant or
breast-feeding patients is not contraindi-
cated.69,71,72,75 Vasoconstrictors commonly are
added to local anesthetics to retard systemic
absorption, increase efficacy and prolong dura-
tion. In general, the concern for pregnant
women involves epinephrine’s α-adrenergic
effects, which may decrease uterine blood flow,
and its β-adrenergic activity, which may
decrease uterine activity and prolong labor.72,81
Vasoconstrictor concentrations in commonly
used preparations include 1:100,000 (0.01 mg
per milliliter) or 1:200,000 (0.005 mg/mL) epi-
nephrine or 1:20,000 (0.05 mg/mL) levonorde-
frin. If careful technique is used to prevent
intravascular injection, a cumulative dose of as
much as 0.1 mg can be used safely in healthy
pregnant patients (the equivalent of five
carpules of dental local anesthetic containing
1:100,000 epinephrine concentration, or 10
carpules containing a 1:200,000 epinephrine
concentration).82 No studies currently exist
describing the use of epinephrine during human
lactation; however, because of its short half-life,
it is unlikely that epinephrine distributes into
breast milk and, therefore, it is not contraindi-
cated for use during lactation.82-84
Neves and colleagues85 studied the effects of
lidocaine with and without epinephrine in 31
pregnant women with rheumatic heart disease.
Their results showed no interferences in mater-
nal blood pressure and heart rate, fetal heart
rate, maternal uterine contractions, fetal body
movement and nonstress test with the use of 1.8
mL of 2 percent lidocaine with 1:100,000 epi-
nephrine. The authors noted a higher frequency
of arrhythmias (defined as > 10 extrasystoles
per hour) in patients who received the vasocon-
strictor versus patients who did not, 42 percent
versus 14 percent, respectively, suggesting an
increased adrenergic response in pregnant
women.
Levonordefrin is the other vasoconstrictor
available in dental local anesthetic carpules. It
is supplied as 1:20,000, a dose commonly consid-
ered equally as potent and efficacious as
1:100,000 epinephrine (epinephrine is five times
as potent as levonordefrin).86 Because of lev-
onordefrin’s disproportionate effects on the
α-adrenergic system (75 percent α-adrenergic
866 JADA 143(8) http://jada.ada.org August 2012
Copyright © 2012 American Dental Association. All rights reserved.
versus 25 percent β-adrenergic effects), it some-
times is considered to possess less vasopressor
activity and to incite less cardiac and central
nervous system stimulation.87 This, however,
has been shown not to be the case in the concen-
trations used in dentistry.88 Levonordefrin has
no FDA pregnancy risk classification; therefore,
its use cannot be recommended, although some
authors have suggested it is safe for women to
use during pregnancy and lactation.69,70,75
Sedatives. Benzodiazepines are the most
commonly used drugs in the United States for
the treatment of anxiety, phobias and tension.89
The effects of using benzodiazepines (such as
alprazolam, diazepam, lorazepam, midazolam
and triazolam) during pregnancy may lead to
fetal abortion, malformations, intrauterine
growth retardation, functional deficits, carcino-
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genesis and mutagenesis, with the greatest
risks occurring between two and eight weeks
after conception.80,81 When these drugs are used
near term, fetal dependence and withdrawal
have been known to occur.89,90 For all of these
reasons, this class of medications is listed by the
FDA as pregnancy risk factor D/X depending on
the particular drug, dose and duration of use.72
Although it did not address triazolam in par-
ticular, the AAP did not consider most benzo-
diazepines to be compatible with breast-
feeding.49 The pump-and-discard strategy for
breast milk described above for short-acting
benzodiazepines such as midazolam and tria-
zolam has been successful for some patients.91
Infant exposure is reduced if breast-feeding is
avoided during times when the mother receives
sedative medications; however, because rela-
tively small amounts of the drug are excreted
into breast milk, some mothers may opt to con-
tinue nursing after weighing the benefits of
breast-feeding against the potential risk to the
infant.
Zaleplon and zolpidem are nonbenzodiaz-
epines that also produce their sedative and hyp-
notic effects via selective stimulation of the α-
subunit of the gamma-amino-butyric acid-A
macromolecular complex.92 If a pregnant or
breast-feeding patient requires an oral sedative
to help her relax throughout her dental appoint-
ment, either of these agents would be preferable
to the benzodiazepines, because they are listed
by the FDA as pregnancy risk factor C. Zaleplon
has not been reviewed, but the AAP49 considers
zolpidem to be safe in regard to breast-feeding.
Emergency medications. β2-adrenergic
receptor agonists. The most common β2-
adrenergic receptor agonist used to treat acute
bronchospasm that may be experienced during

an asthmatic attack or anaphylaxis is albuterol,
administered via inhalation.44 Albuterol relaxes
bronchial smooth muscles and inhibits chemical
mediators released during hypersensitivity
reactions. Unlike other β2-adrenergic receptor
agonists, albuterol is an excellent choice
because it is associated with fewer cardiovas-
cular adverse effects than are other bron-
chodilators.44 Unfortunately, antiasthmatic
drugs such as albuterol are listed by the FDA as
category C medications, although they fre-
quently are used by pregnant women who have
asthma.93 Researchers have observed an in-
crease in the risk of congenital malformation
associated with the use of albuterol during preg-
nancy,94 although findings of previous studies
also have demonstrated that pregnant women
with untreated asthma are at substantially
increased risk of experiencing many adverse
pregnancy outcomes.95,96 In an emergency situa-
tion, the benefits to the mother exceed the risk
to the fetus, and this medication needs to be
administered. In addition, although no pub-
lished data exist regarding the use of albuterol
via inhaler during lactation, data regarding the
related drug, terbutaline, indicate that little is
expected to be excreted into breast milk and,
therefore, the drug should be safe.97
Histamine blockers. Histamine blockers
reverse the actions of histamine by occupying
H1-receptor sites on the effector cell and are
indicated for patients with mild or delayed-
onset allergic reactions. Diphenhydramine typi-
cally is administered as a 50-mg intramuscular
injection followed by 25 to 50 mg orally every
three to four hours for as long as three days
after such a reaction.44 Diphenhydramine is safe
for a pregnant patient, as it is listed by the FDA
as a category B medication. Although the AAP
has not published comments on the use of this
medication during breast-feeding, occasional
small doses of diphenhydramine would not be
expected to cause any adverse effects in breast-
fed infants according to a study by Ito and
colleagues.98
Epinephrine. Epinephrine is the single most
important injectable drug in the emergency
kit.44 Epinephrine is an endogenous cate-
cholamine that stimulates both α- and β-
adrenergic receptors. It is the drug of choice for
treating cardiovascular and respiratory mani-
festations of acute allergic reactions. When
administered in resuscitative dosages, epineph-
rine causes bronchodilation and increased sys-
temic vascular resistance, heart rate, arterial
blood pressure, myocardial contractility, and
myocardial and cerebral blood flow.99 For treat-
Copyright © 2012 American Dental Association. All rights reserved.
CLINICAL PRACTICE
ment of life-threatening signs and symptoms of
an acute allergic reaction, the clinician must
administer epinephrine immediately, injecting
the drug subcutaneously (0.3 to 0.5 mg of a
1:1,000 epinephrine solution) or intramuscu-
larly for a more serious emergency (0.4 to 0.6
mg of the same epinephrine solution). Epineph-
rine is available in ampules as well as in pre-
loaded syringes or autoinjectors for immediate
use.100 Epinephrine also is indicated for the
treatment of acute asthmatic attacks that are
unrelieved by β2-adrenergic receptor agonists
such as albuterol.101
As with albuterol, in an emergency situation,
the benefits of epinephrine use to the mother
exceed the risk to the fetus, and this medication
needs to be administered. In addition, no infor-
mation is available on the use of epinephrine
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during breast-feeding. Because of its poor oral
bioavailability and short half-life, any epineph-
rine in milk is unlikely to affect the infant and
therefore should be safe.102 Epinephrine is listed
by the FDA as pregnancy risk factor C.
Antidotal drugs. If dentists administer opi-
oids or benzodiazepines to induce moderate or
deep sedation or general anesthesia, they must
include antidotal drugs in the emergency kit.44
Naloxone is a specific opioid antagonist that
reverses opioid-induced respiratory depres-
sion.103 Flumazenil is a specific benzodiazepine
antagonist that reverses sedation and respira-
tory depression resulting from benzodiazepine
administration.104 Although both of these med-
ications are listed by the FDA as category C
with respect to use in pregnancy, in an emer-
gency situation, the benefits to the mother
exceed the risk to the fetus and either of these
medications should be administered if indicated.
According to authors of studies involving
nursing mothers, naloxone does not affect lacta-
tion hormone levels.105,106 If a mother requires
naloxone, it is not a reason for her to discon-
tinue breast-feeding.105,106
Flumazenil. Flumazenil has not been
reviewed by the AAP; however, intravenous
flumazenil has been given directly to neonates
to reverse the sedative effects of diazepam
administered to the mother immediately before
delivery without any noted adverse effects.107,108
Administration to a lactating patient would
carry an even lower risk given the short elimi-
nation half-life (mean, 54 minutes), and the
poor oral bioavailability that will further miti-
gate transfer into breast milk.
Nitroglycerin. Nitroglycerin for the dental
office is available as sublingual tablets or trans-
lingual sprays.44 Nitroglycerin is the treatment
JADA 143(8) http://jada.ada.org August 2012 867
CLINICAL PRACTICE

BOX 3 infarction. If the

patient has never
Pregnancy, breast-feeding and drugs used received a diagnosis
in dentistry: key considerations for clinicians of angina pectoris and
and proposed areas for future research. develops symptoms of
a possible acute
KEY CONSIDERATIONS FOR CLINICIANS myocardial infarction,
dThe benefit of continuing medication in pregnancy often outweighs the potential risks such as chest pain or
dPrepregnancy assessment and counseling should be offered to all women of childbearing chest pressure, the
age who are receiving medication
clinician should con-
dClinicians should seek the latest information on specific drugs to allow the pregnant
or breast-feeding dental patient to make an informed choice sider administering
dThe benefit of continuing medication during breast-feeding often outweighs the 0.4 mg of sublingual
potential risks nitroglycerin if the
PROPOSED AREAS FOR FUTURE RESEARCH patient’s systolic
dLarge-scale observational studies of the use of common medications during pregnancy blood pressure is
dStudies that take into account the potential for active disease to affect the fetus adversely acceptable (> 90-100
and the need for clinicians to interpret the benefits and risks regarding the role
of medication accordingly mm of mercury) after
first calling 911

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dStudies regarding the effect of prepregnancy counseling on medication use compliance
during pregnancy
d Large-scale observational studies regarding the effect of paternal medication on fetal
teratogenesis rate
BOX 4
Online resources regarding
drug safety in pregnancy.
Breastfeeding Online
www.breastfeedingonline.com/meds.shtml
National Library of Medicine Drugs and Lactation
Database (LactMed)
http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Organization of Teratology Information Specialists
www.otispregnancy.org
SafeFetus.com
www.safefetus.com
Texas Tech University Health Sciences Center Infant
Risk Center
www.infantrisk.com
U.S. Food and Drug Administration
www.fda.gov
of choice for the patient with angina who may
experience acute chest pain. It acts primarily by
relaxing vascular smooth muscle, dilating sys-
temic venous and arterial vascular beds, which
leads to a reduction in venous return and sys-
temic vascular resistance. These actions of re-
establishing the balance between oxygen supply
and oxygen demand in the coronary circulation
result in the elimination of the chest pain.
If the patient does not bring his or her own
nitroglycerin to the dental office, the clinician
should administer one tablet or metered spray
(0.4 mg). This dosage may be repeated twice at
five-minute intervals for a total of three doses.
Relief should occur within one to two minutes; if
the discomfort is not relieved, the dentist must
consider a diagnosis of evolving myocardial
(emergency assist-
ance) and adminis-
tering aspirin. As
with the other emer-
gency medications previously discussed, the
benefits to the mother exceed the risk to the
fetus and this medication needs to be adminis-
tered. No information is available on the use of
nitroglycerin during breast-feeding, but because
of its short half-life, any nitroglycerin in milk is
unlikely to affect the infant and therefore
should be considered safe.109,110
Future directions and resources. Box 3
highlights the main messages and proposed
areas for future research on these topics; Box 4
offers references to consult when investigating
whether a drug is safe in pregnancy.
CONCLUSIONS
This review highlights common dental drugs to
avoid and drugs that are considered relatively
safe to use in pregnant and breast-feeding
patients. When considering prescribing in preg-
nancy, the dentist must weigh the balance
between risk to the fetus and benefit to the
mother, and the appropriate conclusion should
reflect current evidence. In some cases, medica-
tion dosing should be avoided or altered; how-
ever, there are times when it is unnecessary to
stop or avoid the use of medications. A trusting,
open relationship between the dentist and
patient is of vital importance to optimize the
mother’s treatment during her pregnancy. In
particular, dentists should help pregnant or
breast-feeding patients understand all of the
risks and benefits before they use any pre-
scribed medication, as it is possible to manage
the care of these patients and their conditions
safely. ■

868 JADA 143(8) http://jada.ada.org August 2012

Copyright © 2012 American Dental Association. All rights reserved.

Disclosure. Drs. Donaldson and Goodchild did not report any
disclosures.
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