COVER ARTICLE

Over-the-Counter Medications
in Pregnancy
RONALD A. BLACK, M.D., and D. ASHLEY HILL, M.D.
Florida Hospital Family Practice Residency, Orlando, Florida

Pregnant women commonly use over-the-counter medications. Although most over-

the-counter drugs have an excellent safety profile, some have unproven safety or are
known to adversely affect the fetus. The safety profile of some medications may
change according to the gestational age of the fetus. Because an estimated 10 percent
or more of birth defects result from maternal drug exposure, the U.S. Food and Drug
Administration has assigned a risk category to each drug. Many drugs have not been
evaluated in controlled trials and probably will not be because of ethical considera-
tions. Of the commonly used over-the-counter medications, acetaminophen, chlor-
pheniramine, kaolin and pectin preparations, and most antacids have a good safety
record. Other drugs, such as histamine H2-receptor blockers, pseudoephedrine, and
atropine/diphenoxylate should be used with caution. If use of smoking cessation prod-
ucts is desired, the intermediate-release preparations minimize the amount of nicotine
while maintaining efficacy. With all over-the-counter medications used during preg-
nancy, the benefit of the drug should outweigh the risk to the fetus. (Am Fam Physi-
cian 2003;67:2517-24. Copyright© 2003 American Academy of Family Physicians.)

A
common concern about the has changed dramatically since the early
care of pregnant women 1970s, largely because of the problems
involves the use of over- with thalidomide and diethylstilbestrol.
the-counter (OTC) med- Consequently, extensive testing is
ications. Nonprescription required before a drug can be labeled for
drugs account for about 60 percent of use during pregnancy.
medications used in the United States, Since 1975, the U.S. Food and Drug
and more than 80 percent of pregnant Administration (FDA) has assigned preg-
women take OTC or prescription drugs nancy risk factors to all drugs used in the
during pregnancy.1,2 Of the new OTC United States (Table 1).4 Unfortunately,
drugs marketed between 1975 and 1994, many drugs have not been adequately
30 percent were previously prescription researched during pregnancy and,
medications. because of ethical considerations, proba-
It is estimated that up to 60 percent of bly will not be in the future.
patients consult a health care professional
when selecting an OTC product.1 Many Pain Medications
physicians are cautious in their OTC rec- The most commonly used OTC pain
ommendations because of concern about medications are aspirin, acetaminophen
possible adverse effects on a developing (Tylenol), and nonsteroidal anti-inflam-
fetus. At least 10 percent of birth defects matory drugs (NSAIDs), including
are thought to result from maternal drug ibuprofen (Advil, Motrin), ketoprofen
exposures.3 The issue is complicated by (Orudis), and naproxen (Aleve). The
the fact that the safety and efficacy profile safety of these medications during preg-
of a given medicine often changes during nancy is outlined in Table 2.5,6
the course of a normal pregnancy.2 Acetaminophen is widely used during
See editorial
on page 2476.
The medical community’s approach to pregnancy. Although there is no known
the use of medications during pregnancy association with teratogenicity, few clinical

JUNE 15, 2003 / VOLUME 67, NUMBER 12 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 2517
 TABLE 1
FDA Classification of Drug Safety During Pregnancy

Category A Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester
(and there is no evidence of risk in later trimesters), and the possibility of fetal harm
appears remote.
Category B Either animal reproduction studies have not demonstrated a fetal risk but there are no
controlled studies in pregnant women, or animal reproduction studies have shown an
adverse effect (other than a decrease in fertility) that was not confirmed in controlled
studies in women in the first trimester (and there is no evidence of risk in later trimesters).
Category C Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal
or other) and there are no controlled studies in women, or studies in women and animals
are not available. Drugs should be given only if the potential benefit justifies the potential
risk to the fetus.
Category D There is positive evidence of human fetal risk, but the benefits from use in pregnant women
may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation
or for a serious disease in which safer drugs cannot be used or are ineffective).
Category X Studies in animals or human beings have demonstrated fetal abnormalities or there is evidence
of fetal risk based on human experience, and the risk of the use of the drug in pregnant
women clearly outweighs any possible benefit. The drug is contraindicated in women who
are or may become pregnant.

FDA = U.S. Food and Drug Administration.

Information from Briggs GG, Freeman RK, Yaffe SJ, eds. Drugs in pregnancy and lactation: a reference guide
to fetal and neonatal risk. 5th ed. Baltimore: Williams & Wilkins, 1998:577-8,627-8.

TABLE 2
Use of OTC Pain Medications in Pregnancy

FDA pregnancy
risk classification
by trimester Crosses
Drug name (1st/2nd/3rd) Drug class placenta? Use in pregnancy

Acetaminophen B/B/B Non-narcotic Yes Pain reliever of choice

(Tylenol) analgesic/antipyretic
Aspirin D/D/D Salicylate Yes Not recommended except
analgesic/antipyretic for specific indications*
Ibuprofen (Advil, B/B/D NSAID analgesic Yes Use with caution; avoid in
Motrin) third trimester†
Ketoprofen B/B/D NSAID analgesic Yes Use with caution; avoid in
(Orudis) third trimester†
Naproxen B/B/D NSAID analgesic Yes Use with caution; avoid in
(Aleve) third trimester†

OTC = over-the-counter; FDA = U.S. Food and Drug Administration; NSAID = nonsteroidal anti-inflammatory
drug.
*—Associated with increased perinatal mortality, neonatal hemorrhage, decreased birth weight, prolonged
gestation and labor, and possible teratogenicity.5
†—Associated with oligohydramnios, premature closure of the fetal ductus arteriosus with subsequent per-
sistent pulmonary hypertension of the newborn, fetal nephrotoxicity, and periventricular hemorrhage.6
Information from Collins E. Maternal and fetal effects of acetaminophen and salicylates in pregnancy. Obstet
Gynecol 1981;58(5 Suppl):57S-62S, and Macones GA, Marder SJ, Clothier B, Stamilio DM. The controversy
surrounding indomethacin for tocolysis. Am J Obstet Gynecol 2001;184:264-72.

2518 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 67, NUMBER 12 / JUNE 15, 2003
TABLE 3
OTC Decongestants, Expectorants, and Nonselective Antihistamines in Pregnancy

FDA pregnancy Crosses

Drug name risk classification Drug class placenta? Use in pregnancy

Chlorpheniramine B Antihistamine Not known Antihistamine of choice

(Chlor-Trimeton)
Pseudoephedrine B Sympathomimetic Not known Oral decongestant of choice,10
hydrochloride decongestant possible association with
(Novafed) gastroschisis9
Guaifenesin C Expectorant Not known May be unsafe in first
(Humibid L.A.) trimester*
Dextromethorphan C Non-narcotic Not known Appears to be safe in
hydrobromide antitussive pregnancy
(Benylin DM)
Diphenhydramine B Antihistamine/ Yes Possible oxytocin-like effects
(Benadryl) antiemetic at high dosages
Clemastine B Antihistamine Not known Unknown safety profile
fumarate (Tavist)

OTC = over-the-counter; FDA = U.S. Food and Drug Administration.

*—Possible increased risk of neural tube defects.
Information from Werler MM, Mitchell AA, Shapiro S. First trimester maternal medication use in relation to
gastroschisis. Teratology 1992;45:361-7, and The use of newer asthma and allergy medications during preg-
nancy. The American College of Obstetricians and Gynecologists (ACOG) and the American College of Allergy,
Asthma, and Immunology (ACAAI). Ann Allergy Asthma Immunol 2000;84:475-80.

data are available to support the lack of associ- hypertension of the newborn, fetal nephro-
ation.5 The extensive use of acetaminophen in toxicity, and periventricular hemorrhage.6
pregnancy combined with the paucity of docu- Other NSAIDs, such as ibuprofen, have
mented adverse effects have served to validate been studied less often during pregnancy.
the selection of this medication as the pain However, an analysis8 of 50 pregnant patients
reliever of choice during pregnancy. who overdosed on ibuprofen revealed no evi-
Salicylates have been associated with dence of fetal abnormalities. Because of the
increased perinatal mortality, neonatal hemor- possibility of adverse effects of NSAIDs on the
rhage, decreased birth weight, prolonged ges- fetus, it is our opinion that these medications
tation and labor, and possible birth defects.5 should be used sparingly during pregnancy.
However, one study7 found that low-dose
aspirin is not associated with an increased risk Decongestants, Expectorants,
of abruptio placentae or increased rates of and Antihistamines
perinatal mortality. Pregnant women should Women commonly use cold medications
use salicylates only under the guidance of a during pregnancy. These medications, like
medical professional. most of the other OTC drugs, have not been
Indomethacin (Indocin) is the most studied studied well in pregnancy (Table 3).9,10 As a
NSAID that is commonly used during preg- result, some physicians are disinclined to rec-
nancy. Physicians may employ indomethacin
during pregnancy to treat pain from degener-
ating leiomyomata, or as a tocolytic agent. Because of potential adverse effects on the fetus from use
Unfortunately, indomethacin use during
of salicylates and nonsteroidal anti-inflammatory drugs, aceta-
pregnancy may result in oligohydramnios,
premature closure of the fetal ductus arterio- minophen is the preferred pain reliever during pregnancy.
sus with subsequent persistent pulmonary

JUNE 15, 2003 / VOLUME 67, NUMBER 12 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 2519
 ommend any treatment for the common cold. cians and Gynecologists and the American Col-
The most commonly used cold medications lege of Allergy, Asthma, and Immunology
include decongestants and expectorants such released a position statement10 regarding the
as pseudoephedrine (Novafed), guaifenesin use of asthma and allergy medications, includ-
(Humibid L.A.), and dextromethorphan ing antihistamines and oral decongestants.
(Benylin DM), and the antihistamines diphen- Chlorpheniramine and tripelennamine (PBZ)
hydramine (Benadryl), chlorpheniramine were recommended as antihistamines of
(Chlor-Trimeton), and clemastine fumarate choice. Pseudoephedrine was recommended as
(Tavist). the oral decongestant of choice, based on ani-
The use of vasoconstrictive agents such as mal studies and a large prospective human
pseudoephedrine may activate alpha-adrener- experience with the drug during pregnancy.
gic receptors, elevating blood pressure or However, because pseudoephedrine may be
causing vasoconstriction in the uterine arter- associated with gastroschisis and because other
ies, and potentially adversely affecting blood choices are available, it may be prudent to avoid
flow to the fetus. This process could explain using this medication during the first trimester
the reported association between the use of unless the benefit outweighs the risk.
pseudoephedrine in the first trimester and the Dextromethorphan has been associated
development of gastroschisis.9 This theory is with birth defects in chicken embryos. The
debatable; evidence suggests that this effect is Collaborative Perinatal Project14 monitored
negligible at typical dosages.11 50,282 pregnant women, 300 of whom were
Diphenhydramine is widely used in preg- exposed to dextromethorphan in the first
nancy as a sedative, an antihistamine, and an trimester. Birth defects did not increase above
anti-nausea drug, although few data confirm the baseline rate. Another study15 of 59 women
its safety during pregnancy. The drug has been who had used dextromethorphan in the first
shown to have oxytocin-like effects, especially trimester documented one malformation.
in high dosages.12 In addition, adverse drug Thus, sufficient evidence indicates a lack of
interactions that do not occur in nonpregnant adverse effects of dextromethorphan use dur-
patients may occur in pregnant patients. For ing pregnancy.
example, one study13 showed a significant When used during the first trimester in the
increase in fetal morbidity when diphenhy- presence of a febrile illness, guaifenesin has
dramine was taken in combination with been associated with an increased risk of
temazepam (Restoril). neural tube defects.16 It is unclear whether this
In 2000, the American College of Obstetri- increased risk derives from the medication
use, the illness, or both.
A MEDLINE search using the keywords
“clemastine,” “clemastine and pregnancy,” and
The Authors
“clemastine and teratogen” found no studies
RONALD A. BLACK, M.D., is currently in private practice in Towanda, Pa. He recently addressing the safety or potential teratogenic-
completed a fellowship in family practice obstetrics at Florida Hospital, Orlando. Dr.
Black received his medical degree from Loma Linda University School of Medicine in ity of clemastine fumarate in pregnancy.
Loma Linda, Calif., and completed a residency in family medicine at the Florida Hospi-
tal Family Practice Residency Program. Antidiarrheal Agents
D. ASHLEY HILL, M.D., is associate director of the Department of Obstetrics and Gyne- The most commonly used antidiarrheal
cology at the Florida Hospital Family Practice Residency Program. He received his med- medications include kaolin and pectin prepa-
ical degree from the University of South Florida College of Medicine, Tampa. Dr. Hill
served an internship at Charity Hospital in New Orleans and a residency in obstetrics rations (such as Kaopectate), bismuth subsali-
and gynecology at the University of South Florida College of Medicine. cylate (Pepto Bismol), loperamide (Imod-
Address correspondence to D. Ashley Hill, M.D., 500 E. Rollins St., Suite 201, Orlando, ium),4 and atropine/diphenoxylate (Lomotil).
FL 32803. Reprints are not available from the authors. The safety of the various agents is outlined in

2520 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 67, NUMBER 12 / JUNE 15, 2003
 OTC Drugs in Pregnancy

Table 4.4 Kaolin and pectin preparations are

not absorbed. A possible association has been Because kaolin and pectin preparations are not absorbed,
identified between the ingestion of clays con- they are preferred over bismuth subsalicylate and
taining kaolin and the development of iron
atropine/diphenoxylate products during pregnancy.
deficiency anemia.17 Use of bismuth subsali-
cylate can result in absorption of salicylate and
should be avoided in pregnancy. Loperamide
has not been found to be teratogenic in ani- during pregnancy.19 Data are insufficient to
mals. However, at least one study4 involving determine if these associations are significant.
first-trimester exposure in humans showed a Magnesium compounds contain magnesium
possible increase in fetal cardiac malforma- sulfate, a known tocolytic agent. Despite the
tion. Atropine/diphenoxylate has been found minimal magnesium absorption that occurs
to be teratogenic in animals; however, there is with antacid ingestion, some clinicians prefer
insufficient evidence of teratogenicity in the use of calcium-containing preparations.
human pregnancy.18 Simethicone (Mylanta Gas) is not absorbed.
The histamine H2-receptor blockers are
Antacid Preparations effective in treating symptoms of heartburn
Several antacids are available in OTC forms, and gastroesophageal reflux disease in preg-
including preparations that contain alginic nancy,20 but these drugs readily cross the pla-
acid, aluminum, magnesium, and calcium. All centa.21 Their use is recommended in preg-
of these preparations generally are regarded as nant women whose symptoms cannot be
safe in pregnancy (Table 5). There have been adequately controlled with lifestyle modifica-
sporadic reports of fetal maldevelopment and tion and antacids.22
injury associated with prolonged use of high The most studied H2 blockers are cimeti-
dosages of aluminum-containing antacids dine (Tagamet) and ranitidine (Zantac). Stud-

TABLE 4
OTC Antidiarrheal Medications in Pregnancy

FDA pregnancy
risk classification
by trimester Crosses
Drug name (1st/2nd/3rd) Drug class placenta? Use in pregnancy

Kaolin and pectin B/B/B Antidiarrheal No Antidiarrheal of choice

(Kaopectate) (not absorbed)
Bismuth subsalicylate C/C/D Antidiarrheal Yes Not recommended
(Pepto Bismol) (salicylate absorption)
Loperamide (Imodium) B/B/B Antidiarrheal Not known Probably safe*
Atropine/diphenoxylate C/C/C Antidiarrheal Not known Not recommended
(Lomotil) (adverse animal studies)

OTC = over-the-counter; FDA = U.S. Food and Drug Administration.

*—Possible increase in fetal cardiac malformation with first-trimester use.4
Information from Briggs GG, Freeman RK, Yaffe SJ, eds. Drugs in pregnancy and lactation: a reference guide
to fetal and neonatal risk. 5th ed. Baltimore: Williams & Wilkins, 1998:577-8,627-8.

JUNE 15, 2003 / VOLUME 67, NUMBER 12 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 2521
 TABLE 5
OTC Antacids, Simethicone, and H2-Receptor Selective Antihistamines in Pregnancy

FDA pregnancy Crosses

Drug name risk classification Drug class placenta? Use in pregnancy

Aluminum hydroxide/ B Antacid Not known Generally regarded as safe

magnesium hydroxide
(Maalox)*
Calcium carbonate C Antacid Not known Generally regarded as safe
(Tums)
Simethicone C Antiflatulent No Generally regarded as safe
(Mylanta Gas)
Cimetidine (Tagamet) B Antihistamine Yes Preferred after antacids;
generally regarded as safe
Ranitidine (Zantac) B Antihistamine Yes Preferred after antacids;
generally regarded as safe
Nizatidine (Axid) C Antihistamine Yes Not recommended (adverse
animal studies)
Famotidine (Pepcid) B Antihistamine Yes Probably safe, data needed

OTC = over-the-counter; FDA = U.S. Food and Drug Administration.

*—Contains magnesium sulfate.

ies of these agents generally have shown sig- 18,515 case pregnancies and 32,804 control
nificant improvement of symptoms with no pregnancies did not show an association
significant adverse effects. Animal studies also between fetal malformations and the use of
fail to show an increased fetal risk with the use clotrimazole.
of these medications in pregnancy, the notable Several small trials have indicated that
exception being nizatidine (Axid).22 butoconazole and miconazole are likely to be
Nizatidine has been associated with an safe during the second and third trimesters.
increased risk of fetal death, spontaneous Insufficient data are available regarding the
abortion, and decreased fetal weight in rab- safety of tioconazole in pregnancy.25
bits.22 These studies used the common pre- Many clinicians use oral fluconazole (Diflu-
scription-strength doses. The OTC doses are can) to treat vulvovaginal candidiasis. A study26
one half of the prescription strength. of 226 women exposed to fluconazole during
Although studies have indicated that there is the first trimester of pregnancy revealed that
probably no increased risk of fetal morbidity patients taking fluconazole were no more likely
or mortality, few studies have evaluated first- than unexposed control patients to experience
trimester use of H2 blockers. Therefore, most miscarriage, stillbirth, or congenital anomalies.
investigators recommend avoiding these Ketoconazole (Nizoral), flucytosine (Anco-
drugs in the first trimester.22,23 bon), and griseofulvin (Grisactin) may be ter-
atogenic or embryotoxic in animals.25
Antifungals The Centers for Disease Control and Pre-
The most common antifungal medications vention recommends using only topical vagi-
available as OTC drugs include the imidazole nal antifungal agents (including butoconazole,
agents clotrimazole (Mycelex), butoconazole clotrimazole, miconazole, and the prescription
(Femstat), miconazole (Monistat), and tio- medications terconazole [Terazol] and nystatin
conazole (Vagistat-1). Table 6 23,24 describes the [Mycostatin]) in pregnancy.27 Because imidaz-
safety of various OTC antifungal agents in ole agents are likely to be safe when used dur-
pregnancy. One of the largest studies24 to date ing pregnancy and may be more effective than
investigated the teratogenicity of clotrimazole. nystatin,28 they should be considered as first-
The population-based, case-control study of line therapy in pregnant patients.

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 OTC Drugs in Pregnancy

Smoking Deterrents Histamine H2-receptor blockers should not be used during

Nicotine replacement therapy presents an the first trimester unless symptoms cannot be controlled with
interesting clinical dilemma. Researchers lifestyle modification and antacids.
believe that nicotine and its metabolic by-
product, cotinine, are harmful to the develop-
ing fetus because smoking is known to cause
harmful fetal effects, including intrauterine therapy, particularly because cigarette smoke
growth retardation, premature birth, hyper- contains more than 3,000 different chemicals
viscosity in the newborn, spontaneous abor- that can potentially harm humans, and one of
tion, fetal neurotoxicity, and pulmonary the main components of cigarette smoke is
defects, and an increased risk of sudden infant carbon monoxide, a known fetal toxin. There-
death syndrome.29 For these reasons, the FDA fore, it is reasonable to consider the use of
classifies nicotine as a Pregnancy Category D nicotine replacement products in patients
drug. The primary mechanism of these dele- who cannot maintain smoking abstinence
terious effects is believed to be uteroplacental without pharmacologic intervention.
insufficiency. Reduced perfusion of oxy- If pregnant women require nicotine
genated blood through the placenta at various replacement to quit smoking, the amount of
stages of development may cause the various nicotine administered should be minimized as
manifestations of fetal maldevelopment and much as possible while still maintaining effi-
injury. cacy. Until further research is available, physi-
Physicians should educate pregnant cians should consider recommending the
patients about the harmful effects of smoking intermediate-release nicotine preparations
to themselves and the developing fetus, and (nicotine gum, nicotine spray, and nicotine
help these patients develop a plan for smoking inhaler) rather than the continuous-release
cessation. The safety of nicotine replacement method (nicotine patches).30
products in pregnancy has not been ade-
quately studied. However, smoking is likely to The authors indicate that they do not have any con-
be more harmful than nicotine replacement flicts of interest. Sources of funding: none reported.

TABLE 6
OTC Topical Vaginal Antifungal Medications in Pregnancy

FDA pregnancy Crosses

Drug name risk classification Drug class placenta? Use in pregnancy

Butoconazole (Femstat) C Imidazole antifungal Not known Probably safe

Clotrimazole (Lotrimin) C Imidazole antifungal Not known Safe in second and third trimesters (human
trials),24 first trimester probably safe23
Miconazole (Monistat) C Imidazole antifungal Not known Probably safe
Tioconazole (Vagistat-1) C Imidazole antifungal Not known No data

OTC = over-the-counter; FDA = U.S. Food and Drug Administration.

Information from Lagace E. Safety of first trimester exposure to H2 blockers. J Fam Pract 1996;43:342-3, and Czeizel AE, Toth M, Rock-
enbauer M. No teratogenic effect after clotrimazole therapy during pregnancy. Epidemiology 1999;10:437-40.

JUNE 15, 2003 / VOLUME 67, NUMBER 12 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 2523
OTC Drugs in Pregnancy

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