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 H -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.)
has changed dramatically since the early1970s, largely because of the problemswith thalidomide and diethylstilbestrol.
care of pregnant womeninvolves the use of over-the-counter (OTC) med-
required before a drug can be labeled for
nancy risk factors to all drugs used in the
United States (Table 1).4 Unfortunately,
because of ethical considerations, proba-
patients consult a health care professional
when selecting an OTC product.1 Manyphysicians are cautious in their OTC rec-
fetus. At least 10 percent of birth defects
the fact that the safety and efficacy profile
See editorial on page 2476.
association with teratogenicity, few clinical
TABLE 1 FDA Classification of Drug Safety During Pregnancy
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.
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).
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.
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).
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 guideto 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 OTC = over-the-counter; FDA = U.S. Food and Drug Administration; NSAID = nonsteroidal anti-inflammatorydrug.*—Associated with increased perinatal mortality, neonatal hemorrhage, decreased birth weight, prolongedgestation 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.6Information from Collins E. Maternal and fetal effects of acetaminophen and salicylates in pregnancy. ObstetGynecol 1981;58(5 Suppl):57S-62S, and Macones GA, Marder SJ, Clothier B, Stamilio DM. The controversysurrounding indomethacin for tocolysis. Am J Obstet Gynecol 2001;184:264-72.
TABLE 3 OTC Decongestants, Expectorants, and Nonselective Antihistamines in Pregnancy 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 togastroschisis. 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-
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-
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-doseaspirin is not associated with an increased risk
of abruptio placentae or increased rates of
perinatal mortality. Pregnant women should
use salicylates only under the guidance of a
during pregnancy. These medications, like
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
result, some physicians are disinclined to rec-
nancy. Physicians may employ indomethacinduring pregnancy to treat pain from degener-ating leiomyomata, or as a tocolytic agent. Because of potential adverse effects on the fetus from use 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.
ommend any treatment for the common cold.
cians and Gynecologists and the American Col-
include decongestants and expectorants such
released a position statement10 regarding the
as pseudoephedrine (Novafed), guaifenesin
use of asthma and allergy medications, includ-
ing antihistamines and oral decongestants.
(Benylin DM), and the antihistamines diphen-
Chlorpheniramine and tripelennamine (PBZ)
(Chlor-Trimeton), and clemastine fumarate
choice. Pseudoephedrine was recommended as
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
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
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
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
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
been associated with an increased risk of
neural tube defects.16 It is unclear whether this
In 2000, the American College of Obstetri-
increased risk derives from the medicationuse, the illness, or both.
“clemastine,” “clemastine and pregnancy,” and
“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.
ity of clemastine fumarate in pregnancy.
Black received his medical degree from Loma Linda University School of Medicine inLoma 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-
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
rations (such as Kaopectate), bismuth subsali-
served an internship at Charity Hospital in New Orleans and a residency in obstetricsand gynecology at the University of South Florida College of Medicine.
cylate (Pepto Bismol), loperamide (Imod-ium),4 and atropine/diphenoxylate (Lomotil). Address correspondence to D. Ashley Hill, M.D., 500 E. Rollins St., Suite 201, Orlando,FL 32803. Reprints are not available from the authors.
The safety of the various agents is outlined in
OTC Drugs in Pregnancy Table 4.4 Kaolin and pectin preparations arenot 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 andshould be avoided in pregnancy. Loperamidehas 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
possible increase in fetal cardiac malforma-
sulfate, a known tocolytic agent. Despite the
tion. Atropine/diphenoxylate has been found
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.
Simethicone (Mylanta Gas) is not absorbed. 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
safe in pregnancy (Table 5). There have been
adequately controlled with lifestyle modifica-
sporadic reports of fetal maldevelopment and
injury associated with prolonged use of high
dine (Tagamet) and ranitidine (Zantac). Stud-
TABLE 4 OTC Antidiarrheal Medications in Pregnancy FDA pregnancy risk classification by trimester OTC = over-the-counter; FDA = U.S. Food and Drug Administration.*—Possible increase in fetal cardiac malformation with first-trimester use.4Information from Briggs GG, Freeman RK, Yaffe SJ, eds. Drugs in pregnancy and lactation: a reference guideto fetal and neonatal risk. 5th ed. Baltimore: Williams & Wilkins, 1998:577-8,627-8.
TABLE 5 OTC Antacids, Simethicone, and H -Receptor Selective Antihistamines in Pregnancy OTC = over-the-counter; FDA = U.S. Food and Drug Administration.
ies of these agents generally have shown sig-
18,515 case pregnancies and 32,804 control
significant adverse effects. Animal studies also
between fetal malformations and the use of
fail to show an increased fetal risk with the use
of these medications in pregnancy, the notable
butoconazole and miconazole are likely to be
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-
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.
Ketoconazole (Nizoral), flucytosine (Anco-
bon), and griseofulvin (Grisactin) may be ter-atogenic or embryotoxic in animals.25
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 623,24 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
OTC Drugs in Pregnancy Smoking Deterrents Histamine H -receptor blockers should not be used duringthe 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 causeharmful 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
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-
terious effects is believed to be uteroplacental
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-
cacy. Until further research is available, physi-
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
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
Safe in second and third trimesters (human
trials),24 first trimester probably safe23
OTC = over-the-counter; FDA = U.S. Food and Drug Administration.Information from Lagace E. Safety of first trimester exposure to H 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. OTC Drugs in Pregnancy
A. First-trimester drug use and congenital disor-ders. Obstet Gynecol 1985;65:451-5.
1. Jacobs LR. Prescription to over-the-counter drug
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Maternal illness, including fever and medication
use as risk factors for neural tube defects. Teratol-
2. Matt DW, Borzelleca JF. Toxic effects on the female
reproductive system during pregnancy, parturition,
17. Patterson EC, Staszak DJ. Effects of geophagia
and lactation. In: Witorsch R J, ed. Reproductive
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tocolysis. Am J Obstet Gynecol 2001;184:264-72.
21. Dicke JM, Johnson RF, Henderson GI, Kuehl TJ,
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Schenker S. A comparative evaluation of the trans-
Cliver SP. Low-dose aspirin: lack of association with
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Letter to the Editor Rhabdomyolysis and Acute Renal Graft Impairment in a Patient Treated with Simvastatin, Tacrolimus, and Fusidic Acid Peter Kotanko Waltraud Kirisits Falko SkrabalDepartment of Internal Medicine, Krankenhaus der Barmherzigen Brüder, Graz, Austriapost-transplant the following postoperativeis a frequent metabolic disease following re-nal grafting, and atherosclerotic