Download selecting drugs for the pregnant dental patient

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ARTICLE 3
SELECTING DRUGS FOR THE PREGNANT DENTAL PATIENT
PAUL A. MOORE, D.M.D., PH.D.
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When treating pregnant patients,
dental practitioners should avoid
prescribing some drugs routinely
used for local anesthesia, sedation, analgesia or infection.
Dental practitioners need to determine that the potential benefits of the drug required for the
mother’s dental care outweigh
the risks to her fetus. This article
briefly reviews the relative risks
of therapeutic agents commonly
used in dental care to help practitioners select the safest drugs
for use by pregnant patients.
The selection of dental therapeutic agents for local anesthesia, se-
dation, postoperative pain control and treatment of infections is usually straightforward. For healthy young adults, dental practitioners
might routinely select lidocaine hydrochloride with epinephrine, diazepam, codeine with acetaminophen and penicillin V-potassium.
The use of alternative agents may be necessary for patients who
have a history of drug allergy or who are medically compromised, extremely young or old, taking concomitant medications or pregnant.
In the case of a pregnant patient, the dental practitioner must determine that the potential benefits of the dental therapy required for
her care outweigh the risks to the fetus.
Although most elective dental procedures can be postponed until
after the pregnancy is over, dental treatment for a pregnant woman
who has oral pain, advanced disease or infection should not be delayed. It is understood that none of the drugs used to treat pain and
infection are totally without risk. The consequences of not treating an
active infection during pregnancy, however, outweigh the possible
risks presented by most of the drugs required for dental care. This article reviews the concerns associated with drug therapy for pregnant
patients and provides a guide for selecting local anesthetics, peripherally acting analgesics, centrally acting opioids analgesics, antibiotics
and sedatives/anxiolytics for use during pregnancy (Table).
PREGNANCY-RELATED PHYSIOLOGICAL CHANGES
Physiological changes that occur during pregnancy include weight
gain, positional hypotension when placed in a supine position, frequent need to urinate, restricted respiratory function, potential for
hypoglycemia and increased cardiac output sometimes associated
with tachycardia and heart murmurs. Syncope and morning sickness also are common features of pregnancy.
Changes in oral physiology seen during pregnancy include gingival inflammation and hypertrophy, as well as generalized tooth mobility.1,2 Higher anxiety levels associated with pregnancy may intensify the stress of a dental appointment. Dental care during
pregnancy should accommodate these changes with short appointments, avoidance of prolonged supine positioning, oral hygiene and
dietary instructions, and judicious use of radiographs.2
JADA, Vol. 129, September 1998
Copyright ©1998-2001 American Dental Association. All rights reserved.
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CLINICAL PRACTICE
A goal of any drug therapy
prescribed during pregnancy is
to avoid adverse drug reactions
in either the mother or the
fetus. Hypersensitivity, allergies
or toxic reactions that occur in a
woman may compromise her
health and limit her ability to
support a pregnancy. Adverse
drug effects that are specific to
the health of the fetus include
congenital defects, miscarriage,
complications during delivery,
low birth weight and postnatal
drug dependence. These effects
are usually specific to the timing
of the drug administration—during the first, second or third
trimester—the dosage and the
duration of therapy. Dental therapies, which usually use drugs
with short metabolic half-lives
administered for limited periods,
are, therefore, less likely to cause
complications during pregnancy.
The U.S. Food and Drug
Administration, or FDA, has established five categories for classifying drugs according to the risks
they pose to pregnant women and
their fetuses.3 The five categories
provide a guide to the relative
safety of drugs prescribed to pregnant women. Category A includes
drugs that have been studied in
humans and have evidence supporting their safe use. Category B
drugs show no evidence of risk in
humans. Category C includes
drugs for which teratogenic risk
cannot be ruled out. Category D
includes drugs that have demonstrated risks in humans, and category X includes agents that have
been shown to be harmful to the
mother or fetus. Drugs in categories A and B generally are considered appropriate for use during
pregnancy. Category C drugs
should be used with caution, and
drugs in categories D and X
should be avoided or are contraindicated. Less than 20 percent
1282
of all drugs classified by the FDA
fall into categories A or B.4
Product information sheets provided with prescription and nonprescription drugs, as well as drug
information found in Physicians’
Desk Reference, generally include
these FDA use-in-pregnancy ratings.5
Of the thousands of drugs
marketed, only a few drugs are
known for certain to be teratogenic in humans.6,7 Thalidomide,
developed in the 1950s as a tranquilizer and antiemetic, is the
most well-known and prototypic
human teratogen. Thalidomide’s
teratogenesis is unusual because, when the drug is taken
during the first three months of
pregnancy, it induces a very
high incidence of birth defects,
including a unique anomaly
called phocomelia that is charac-
Dental therapies,
which usually use
drugs with short
metabolic half-lives
administered for limited periods, are less
likely to cause complications during
pregnancy.
terized by shortened arms and
legs. Warfarin, retinoids, anticonvulsants and heavy metals
also are known to produce significant physical birth defects.
Fetal alcohol syndrome is associated with varying degrees of
mental retardation in infants
and is thought to be responsible
for as much as 8 percent of the
cases of mental retardation in
the United States.7 Our knowledge of the risks associated with
drug therapy during pregnancy
is most clear when the frequency
of birth defects is high and the
outcome is easily identified.
Adverse effects of drug therapy
during pregnancy that are subtle
and delayed, such as minor
changes in behavior and intelligence, are nearly impossible to
determine.7,8
Many factors may contribute to
uncertainty when determining the
risks of drug therapy. Animal
data, which are usually collected
from studies that use extraordinarily high and prolonged exposures to drugs, are known to vary
markedly by species. For some
congenital defects, such as cleft lip
with or without cleft palate, there
are many possible causes, which
complicates the assessment of
added risk for any specific drug.9
The teratogenic potential for some
drugs may be dependent on a genetic predisposition involved in
fetal development.10 For many
drugs that are new or infrequently
prescribed, accurate assessment of
human risk is impossible.
Additionally, when multiple birth
defects are reported, it is often difficult to determine whether the
drug or the underlying disease requiring drug therapy is the etiologic factor.
RISKS ASSOCIATED WITH
SPECIFIC DRUG CLASSES
Local anesthetics. Most local
anesthetics have not been
shown to be teratogenic in humans and are considered relatively safe for use during pregnancy. The recommendation for
caution (category C) when prescribing mepivacaine hydrochloride and bupivacaine hydrochloride relates primarily to limited
data collected in animal teratogenicity studies. As such, adverse drug effects to humans
cannot be ruled out for these
agents. Because all local anesthetics can cross the placenta
JADA, Vol. 129, September 1998
Copyright ©1998-2001 American Dental Association. All rights reserved.
CLINICAL PRACTICE
TABLE
DENTAL THERAPEUTICS FOR PREGNANT PATIENTS.
DRUG
Generic Name
PRC*
POSSIBLE NEGATIVE
PREGNANCY OUTCOME
Brand Name Examples (Manufacturer)
Local Anesthetics
Bupivacaine
hydrochloride
Marcaine (Eastman Kodak), Sensorcaine
(Astra USA, Inc., Pharmaceuticals)
C
Etidocaine
hydrochloride
Duranest (Astra USA, Inc., Pharmaceuticals)
B
Lidocaine
hydrochloride
Xylocaine (Astra USA, Inc., Pharmaceuticals)
B
Mepivacaine
hydrochloride
Carbocaine (Eastman Kodak), Polocaine (Astra
USA, Inc., Pharmaceuticals)
C
Prilocaine
hydrochloride
Citanest (Astra USA, Inc., Pharmaceuticals)
B
Acetaminophen
Tylenol (McNeil Consumer Products)
Aspirin
Bayer (Sterling Drug Inc.), Bufferin (BristolMyers Company), Ecotrin (SmithKline Beecham
Consumer)
C (3D)†
Ibuprofen
Advil (Whitehall Laboratories), Motrin (McNeil
Consumer Products Co.)
B (3D)
Delayed labor and prolonged
pregnancy in mother
Naproxen
Aleve (Procter & Gamble), Anaprox (Roche
Laboratories)
B (3D)
Delayed labor and prolonged
pregnancy in mother
Codeine with
acetaminophen
Tylenol with codeine (McNeil Laboratories)
C (3D)
Multiple birth defects, neonatal
respiratory depression, neonatal
opioid withdrawal
Hydrocodone
bitartrate and
acetaminophen
Vicodin (Knoll Laboratories)
C (3D)
Neonatal respiratory depression,
neonatal opioid withdrawal
Hydrocodone bitartrate and ibuprofen
Vicoprofen (Knoll Laboratories)
C (3D)
Neonatal respiratory depression,
neonatal opioid withdrawal
Oxycodone with
acetaminophen
Percocet (Dupont Pharmaceuticals), Tylox
(McNeil Laboratories)
C (3D)
Neonatal respiratory depression,
neonatal opioid withdrawal
Fetal bradycardia
Fetal bradycardia
Peripherally Acting Analgesics
B
Postpartum hemorrhage and delivery complications in
mother and fetus
Centrally Acting Opioid Anesthetics
Antibiotics
Amoxicillin
Amoxil (SmithKline Beecham), Polymox
(Bristol-Myers Squibb)
B
Cephalexin
Keflex (Dista)
B
Chloramphenicol
Chlormycetin (Parke-Davis)
X
Clindamycin
hydrochloride
Cleocin (Pharmacia & Upjohn)
B
Doxycycline hyclate
Doryx (Parke-Davis), Vibramycin (Pfizer
Laboratories)
D
Erythromycin base
E-Mycin (Knoll Laboratories), ERYC (Parke-Davis)
Erythromycin
estolate
Ilosone (Lilly),
Erythromycin
ethylsuccinate
E.E.S. (Abbott Laboratories)
Gentamicin
Garamycin (Shering Co.)
Metronidazole
Flagyl (Searle & Co.)
B
Penicillin V-potassium
Pen-Vee K (Wyeth-Ayerst)
B
Maternal toxicity and gray syndrome
and possible death in infant
Tooth discoloration, inhibition of
bone development in infant
B
B‡
Increased risk of maternal
cholestatic hepatitis
B
C (3D)
Potential ototoxicity in fetus
Sedatives/Anxiolytics
Benzodiazepines (for Valium (Roche Laboratories), Xanax
(Pharmacia & Upjohn)
example, diazepam
and alprazolam)
Nitrous oxide
D
Possible oral clefts in fetus
with prolonged exposure
Not
Classified
Spontaneous abortions and
delayed fertility in mother
* PRC: Pregnancy risk category. Category A: drugs that have been studied in humans and have evidence supporting their safe use. Category B: drugs
that show no evidence of risk in humans. Category C: drugs for which teratogenic risk cannot be ruled out. Category D: drugs that have demonstrated
risks in humans. Category X includes agents that have been shown to be harmful to the mother or fetus.
† A category in parentheses (for example, 3D) refers to risk for use during the third trimester of pregnancy.
‡ Use of erythromycin base rather than the estolate salt is recommended.
JADA, Vol. 129, September 1998
Copyright ©1998-2001 American Dental Association. All rights reserved.
1283
CLINICAL PRACTICE
and cause fetal depression, limiting the dose to the minimum
required for effective pain control is obviously advisable.
Epinephrine, a naturally occurring hormone, is generally considered to have no teratogenic
effects when administered with
dental anesthetics.1,11 Because
epinephrine is known to stimulate cardiovascular function, its
administration demands careful
technique and proper dosing.
Peripherally acting analgesics. The peripherally acting
class of analgesics includes a
number of commonly used
agents that should be avoided.
When acetaminophen is administered in therapeutic doses, it
generally is considered to be the
best choice for managing oral-facial pain during pregnancy.7,11,12
Aspirin should be avoided—particularly late in pregnancy—because it is associated with delivery complications and
postpartum hemorrhage in the
mother.13 Chronic use of aspirin
early in the pregnancy has been
associated with anemia in pregnant women.
Aspirin and the newer nonsteroidal anti-inflammatory
drugs, or NSAIDs, such as
ibuprofen and naproxen, have
the common mechanism of inhibiting prostaglandin synthesis. By blocking synthesis of the
prostaglandins involved in induction of labor, NSAIDs may
prolong pregnancy. Additionally, prostaglandin inhibitors
may cause constriction of the
ductus arteriosus in the fetus,
resulting in pulmonary hypertension in the infant. Therefore,
aspirin and any of the other
NSAIDs should be avoided, particularly during the third
trimester of pregnancy.13
The synthetic prostaglandin
analog misoprostol (Cytotec, G.D.
1284
Searle & Co.) has recently been
marketed to prevent gastric ulcers induced by chronic NSAID
therapy. NSAIDs decrease
prostaglandin levels in the gastric mucosa to below the amount
needed to maintain the mucous
layer, which protects the stomach from acid degradation.
Misoprostol restores the gastric
prostaglandin levels, thereby
preventing this common adverse
reaction to chronic NSAID therapy.14 Misoprostol, however, is
very effective in inducing labor
The peripherally acting class of analgesics includes a
number of commonly
used agents that
should be avoided.
and is known to have significant
abortifacient properties.15 The
use of misoprostol to prevent gastric ulcers during NSAID therapy is rarely necessary in acute
dental therapy, and it never
should be administered to pregnant women or women with
childbearing potential.
Centrally acting opioid
analgesics. Opioid analgesics
should be used cautiously and
only when indicated. The use of
codeine and propoxyphene during pregnancy has been evaluated as part of the Collaborative
Perinatal Project.16 This
prospective study monitored
41,337 pregnancies for possible
drug-related birth defects and
toxicities. The results suggested
that codeine and propoxyphene
are associated with multiple
congenital defects, including
heart defects and cleft lip or
palate. Because other opioids,
such as oxycodone and hydrocodone, are administered in-
frequently during pregnancy,
little is known about their risks
to fetuses. As discussed in the
introduction to this article, the
medical disorders that necessitated the use of these opioids
also may have induced heart defects and cleft lip or palate.
Neonatal respiratory depression
and opioid withdrawal also have
been reported with opioid use.10
The prolonged or high-dose use
of opioids late in pregnancy significantly increases the risk of
the fetus developing heart defects or cleft lip or palate.
Antibiotics. The penicillin
and cephalosporin antibiotics
most commonly used in dentistry—penicillin V-potassium,
amoxicillin and cephalexin—are
generally thought to be safe to
prescribe during pregnancy.
Clindamycin, metronidazole and
erythromycin also are believed
to have minimal risk.
Erythromycin estolate may be
more likely to induce hepatic
toxicity in a pregnant patient
and, therefore, is not recommended.17 The greatest concern
regarding antibiotic use is with
agents that have limited indications in dentistry. Aminoglycosides, such as gentamicin,
may induce ototoxicity in the
fetus when administered late in
pregnancy. Tetracyclines, including doxycycline hyclate,
have been implicated for causing tooth discoloration and inhibition of bone development in
infants. Chloramphenicol is contraindicated in pregnancy because of maternal toxicity and
fetal circulatory failure, called
gray syndrome.10,13,16
Sedatives/anxiolytics.
Administration of any of the central nervous system depressants
commonly used for sedation is
problematic. Because sedative
agents inhibit neuronal function
JADA, Vol. 129, September 1998
Copyright ©1998-2001 American Dental Association. All rights reserved.
CLINICAL PRACTICE
and generally cross placental barriers, their use during pregnancy
is generally viewed with apprehension. Of the antianxiety drugs
that are commonly prescribed, the
benzodiazepine diazepam has
been assessed most frequently.
Investigations of both animals
and humans have noted an association between diazepam exposure during pregnancy and oral
clefts.18,19 Yet, confirmation of
these reports has not always been
possible.20,21 A single exposure to a
clinically acceptable dose of any
benzodiazepine as compared with
chronic therapy throughout a
pregnancy would have minimal
risk for teratogenicity.22,23 Overall,
the evidence cautions against prolonged use of all benzodiazepines
during pregnancy.
Prolonged high-dose exposure
to nitrous oxide in rats has produced skeletal and behavioral
teratogenic effects.8,24,25
Additionally, occupational exposure to nitrous oxide has been
observed in spontaneous abortions and reduced fertility in humans.26,27 Nitrous oxide blocks
the vitamin B12-dependent enzyme methionine synthase,
thereby depleting tetrahydrofolate, which is necessary for deoxyribonucleic acid synthesis.
Thus, prolonged exposure to ambient concentrations of nitrous
oxide could conceivably inhibit
cell division.28 Short exposure
during general anesthesia to
agents, such as nitrous oxide, is
not thought to be teratogenic.29
Nevertheless, because nitrous
oxide may inhibit cell replication, minimizing prolonged use
when possible is prudent.
CONCLUSION
Drug and chemical exposure
during pregnancy is believed to
account for only about 1 percent
of congenital malformations.6
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Delivery complications and
birth defects are more commonly caused by the mother’s poor
nutrition, smoking, alcohol consumption, disease, genetic predisposition and age.10,30
Maintaining a healthy lifestyle,
including optimal oral health, is
essential for women who are
currently pregnant or who are
planning to become pregnant.
For example, recent evidence
has implicated periodontal infections as a possible factor associated with the delivery of
low-birth-weight babies.31
Dental practitioners should
provide essential care for pregnant patients, particularly when
acute infections are present. In
this article, the current knowledge about safe drug therapy during pregnancy has been reviewed
and recommendations specific to
dental therapy
have been provided. When
dental treatment is needed
to maintain a
pregnant
Dr. Moore is a prowoman’s
oral
fessor of pharmacology, Department of
health, selecting
Dental Public Health,
the safest
614 Salk Hall,
University of
agents, limiting
Pittsburgh, School of
the duration of
Dental Medicine,
the drug regiPittsburgh, Pa.
15261. Address
mens and minireprint requests to
mizing dosages
Dr. Moore.
are the fundamental principles of
safe therapy. ■
A patient pamphlet entitled “Pregnancy and
Oral Health” provides advice on nutrition, oral
hygiene, gingivitis, drug use, radiographs and
dental care during pregnancy. It can be obtained through the ADA Salable Products
Catalog by calling 1-800-947-4746.
Specific drug therapy information can be obtained from the ADA Council on Scientific
Affairs by calling 1-312-440-2878; ADA members can call the toll-free number on the back
of their membership cards and ask for
Extension 2878.
A national information service for drug safety during pregnancy that provides practitioners with local referrals is available through the
Organization of Teratology Information
Services by calling 1-801-328-2229 or visiting
its Web site at “http://orpheus.ucsd.edu/otis/”.
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CLINICAL PRACTICE
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JADA, Vol. 129, September 1998
Copyright ©1998-2001 American Dental Association. All rights reserved.