American Journal of Obstetrics and Gynecology (2005) 193, 7717

www.ajog.org

Use of over-the-counter medications during pregnancy

Martha M. Werler, ScD,a,* Allen A. Mitchell, MD,a Sonia Hernandez-Diaz, MD, DrPH,a
Margaret A. Honein, PhD,b and the National Birth Defects Prevention Studyb
Slone Epidemiology Center at Boston University, Boston, MAa; Division of Birth Defects and Developmental
Disabilities, Centers for Disease Control and Prevention, Atlanta, GAb
Received for publication October 18, 2004; revised February 4, 2005; accepted February 17, 2005

KEY WORDS
Pregnancy
Medication
Epidemiology

Objective: The most common medications used in pregnancy are nonprescription or over-thecounter medications, although there has been little research on their risks or safety. We describe
the patterns of over-the-counter medication use among pregnant women.
Study design: Data were collected in 2 case-control studies of birth defects: the Slone
Epidemiology Center Birth Defects Study (BDS) and the National Birth Defects Prevention
Study (NBDPS).
Results: Among 7563 mothers of malformed and nonmalformed offspring in the Slone
Epidemiology Center Birth Defects Study and 2970 mothers of nonmalformed offspring in the
National Birth Defects Prevention Study, acetaminophen, ibuprofen, and pseudoephedrine were
used by at least 65%, 18%, and 15%, respectively. Among women in the Slone Epidemiology
Center Birth Defects Study, the use in pregnancy of aspirin and chlorpheniramine decreased from
1976 to 2004 and of ibuprofen, pseudoephedrine, diphenhydramine, dextromethorphan, and
guaifenesin increased. Among women in the National Birth Defects Prevention Study, the use of
acetaminophen, pseudoephedrine, diphenhydramine, and guaifenesin was higher during pregnancy than before pregnancy.
Conclusion: Findings show that over-the-counter medications are used by most pregnant women.
Studies that examine specific over-the-counter medications in relation to specific birth defects are
necessary to better inform pregnant women about risks and safety.
2005 Mosby, Inc. All rights reserved.

Ever since the thalidomide tragedy, there has been

concern that medication use in pregnancy can cause
adverse fetal outcomes. Indeed, other medications have
since been identied as teratogens, such as the antico-

Supported by a cooperative agreement from the Centers for

Disease Control and Prevention.
* Reprint requests: Martha M. Werler, ScD, Slone Epidemiology
Center at Boston University, 1010 Commonwealth Ave, Boston, MA
02215.
E-mail: mwerler@slone.bu.edu
0002-9378/$ - see front matter 2005 Mosby, Inc. All rights reserved.
doi:10.1016/j.ajog.2005.02.100

agulant warfarin,1 the anticonvulsant valproic acid,2

and the acne medication isotretinoin.3 Because each of
these medications requires a prescription, the identication of associated fetal eects was facilitated by medical
record or pharmacy documentation. For over-thecounter (OTC) medication use in pregnancy, the only
conrmed association is between late pregnancy aspirin
use and intracranial hemorrhage in the newborn infant.4
There is a dearth of studies on OTC drugs, in part
because approaches to the study of their potential fetal
eects are complicated by the lack of a paper trail. In

772

Werler et al

Table

Prevalence of specific OTC medication use in pregnancy

Trimester (%)

Medication

BDS*
Pregnancy (%)

NBDPSy
Pregnancy (%)

Prepregnancy (%)z

First

Second

Third

Analgesic
Acetaminophen
Ibuprofen
Aspirin
Naproxen
Decongestant
Pseudoephedrine
Other decongestant
Antihistamine
Chlorpheniramine
Diphenhydramine
Loratadine
Doxylamine
Brompheniramine
Cough medication
Guaifenesin
Dextromethorphan

76.1
69.8
24.8
8.0
4.3
27.7
25.1
2.6
14.8
4.3
7.8
2.9
1.1
0.4
12.9
9.2
8.0

70.4
65.5
18.4
4.3
4.0
16.0
15.4
0.9
7.5
3.0
2.9
1.9
1.4
0.5
8.8
6.2
3.4

56.9
47.6
21.1
4.2
5.3
5.8
5.5
0.3
4.3
1.2
1.0
1.2
0.9
0.2
2.6
0.9
1.6

59.3
54.2
16.0
3.8
3.5
8.1
7.9
0.3
5.3
1.5
1.6
1.3
0.9
.02
3.5
2.1
1.7

46.5
50.5
8.2
2.0
1.7
8.9
8.4
0.6
4.7
1.6
1.4
1.1
0.5
.02
3.5
2.8
1.4

51.5
48.0
8.6
2.1
1.6
6.3
5.9
0.4
3.8
1.0
1.8
0.7
0.3
.01
2
1.8
0.8

* A total of 7563 mothers of offspring with and without birth defects were interviewed between 1998 and 2004.
y
A total of 2970 mothers of offspring without birth defects whose estimated date of delivery was between 1997 and 2001.
z
Prepregnancy period is the 3 months before the estimated date of conception.

granting OTC approval, the US Food and Drug Administration might take available data on pregnancy
exposures and fetal outcomes into consideration, but
adequate evidence, particularly on safety for specic
birth defects, typically is not available. Hence, although
the availability of a drug as an OTC product may reect
safety for its use by the nonpregnant population, it does
not necessarily extend to safety for use during pregnancy. Nonetheless, the general perception that OTC
medications are safe for the general public and therefore
safe for pregnant women may have led, in part, to large
proportions of pregnant women taking these products.
Conversely, this ignorance about the safety of OTCs can
raise concerns about risks to the fetus among the many
women who take an OTC medication before recognizing
that they are pregnant.
We describe the extent of OTC medication use during
pregnancy and discuss the potential public health
implications.

Material and methods

Since 1976, the Boston University Slone Epidemiology
Center Birth Defects Study (BDS) has been interviewing
the mothers of infants with a range of birth defects.
During this time, the study has interviewed O23,000
mothers of ospring with and without birth defects from
the greater metropolitan areas of Boston (1976-present),
Philadelphia (1977-present), Toronto (1978-present),
and San Diego (2001-present). Cases with major structural birth defects are identied from birth, and tertiary

care hospitals and control subjects without birth defects

from the same catchment areas are identied within 5
months after delivery. Mothers are interviewed by
trained nurses within 6 months after delivery in person
(1976-mid 1998) or by telephone (mid 1998-present).
Standardized questions are asked about demographic,
reproductive, and medical factors; behaviors (eg, smoking, alcohol use); diet; and medication use. Information
on medication use is obtained by questions on drugs
taken for a list of illnesses (eg, cold, u, cough, sinus
infection, or congestion), on categories of medications
(eg, nasal sprays), and on selected specically named
medications (eg, Tylenol, Sudafed, Advil, Aleve). For
reported medications, women are asked to retrieve the
package, if possible. In 1999, a medication identication
booklet was introduced, with color images of O350
specic OTC products. Women who reported the use of
a cough, cold, or analgesic product were asked to refer
to the booklet to help them identify which specic
product they had taken. The use of generic forms of
medications also were recorded.
The National Birth Defect Prevention Study
(NBDPS) is an on-going population-based case-control
study of birth defects.5 Case subjects with major structural malformations and a random sample of control
infants (live births with no major birth defects) whose
estimated date of delivery was from November 1997
onward are identied in Arkansas, California, Iowa,
Georgia, Massachusetts, New Jersey, New York, North
Carolina, Texas, and Utah. Standardized interviews of
case and control mothers are conducted by trained

Werler et al

773

Figure 1 Secular trends of specic OTC medication use in the rst trimester among 20,251 Birth Defects Study mothers of
ospring with and without birth defects.

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Werler et al

Figure 2 Analgesic, decongestant, and antihistamine use in pregnancy by maternal demographic factors among 2970 mothers of
ospring without birth defects in the National Birth Defects Prevention Study.

interviewers by telephone within 24 months after the

estimated date of delivery about a range of factors that
are similar to those in the BDS. Questions are asked
about medications that were taken for specic illnesses
(eg, cold or u) and about specically named products
(eg, Tylenol, Advil, Aspirin, Aleve).
For women in both the BDS and the NBDPS, reported
products were linked to their active ingredients by the
Slone Epidemiology Center Drug Dictionary. This tool
allowed us to examine all agents that are typically taken as
OTC medications. For example, a report of Tylenol
Allergy medication would be considered exposure to
acetaminophen, pseudoephedrine, and chlorpheniramine, which are its 3 active components. We included
all exposures to all agents that are available OTC, even
when such an agent may have been prescribed. Information on dose was not collected. In the BDS, pregnancy is
dened as the period beginning with the last menstrual
period and ending at delivery. In the NBDPS, pregnancy is
dened as the period beginning 2 weeks after the last
menstrual period and ending at delivery. BDS data were
restricted to participants from the Boston and Philadelphia centers because, in Canada, overall use tends to be
less common and dierent products are available and

because San Diego became part of the study only recently

(2001). Mothers of ospring with and without birth
defects are combined for this analysis, because rates of
use of specic medications were not appreciably dierent
between the 2 groups. For an examination of recent rates
of medication use during pregnancy, data on 7563 BDS
participants who were interviewed between 1998 and 2004
were included. For an examination of secular trends of
medication use, data on 20,251 BDS participants who
were interviewed between 1976 and 2004 were included.
NBDPS data were restricted to Arkansas, California,
Iowa, Georgia, Massachusetts, New Jersey, New York,
and Texas because North Carolina and Utah became part
of the study only recently (2003). Interviews of 2970
mothers of non-malformed live births who were delivered
between October 1997 and June 2001 were included
for this analysis. For both studies, OTC medications
excluded vitamin, mineral, and herbal products.

Results
In the 1998 to 2004 BDS data, the top 10 medications
that were taken in pregnancy, in rank order, were
acetaminophen, ibuprofen, pseudoephedrine, aspirin,

Werler et al

775

Figure 3 Adjusted (for maternal race or ethnicity, age, and years of education) rates of analgesic, decongestant, and antihistamine
use by state among 2970 mothers of ospring without birth defects in the National Birth Defects Prevention Study.

naproxen, diphenhydramine, guaifenesin, albuterol,

amoxicillin, and dextromethorphan. In the 1997 to
2001 NBDPS data, the corresponding medications
were acetaminophen, ibuprofen, antibiotics (not otherwise specied), amoxicillin, pseudoephedrine, naproxen,
guaifenesin, aspirin, diphenhydramine, and chlorpheniramine. In both the BDS and NBDPS, 8 of the top 10
products were available OTC. We compared the prevalence of use in pregnancy of OTC categories and
specic agents for overlapping periods of the BDS and
NBDPS (Table). In both studies, acetaminophen was
the most commonly taken product, with at least 65.5%
of women taking it at some point during pregnancy.
Ibuprofen and pseudoephedrine were the next most
commonly used products, with at least 15% of women
exposed in pregnancy. Aspirin and naproxen were used
less commonly, but they were nonetheless used by at
least 4% of women. Cough medicines and antihistamines were used by at least 7% of women.
Also included in Table is OTC medication use
among NBDPS women by trimesters of pregnancy and
the 3-month period before the onset of pregnancy.
Among analgesic products, there was a 5% decrease in
ibuprofen use and a 2% decrease in naproxen use
between prepregnancy and the rst trimester of preg-

nancy. These decreases in use were countered by a 7%

increase in the use of acetaminophen during the same
time frame. The use of all 4 analgesic agents (acetaminophen, ibuprofen, naproxen, and aspirin) decreased
from the rst to the second and third trimesters. Among
the cold, allergy, and cough medications, pseudoephedrine and guaifenesin use increased from prepregnancy
to the second trimester, then decreased in the third
trimester. With the exception of diphenhydramine, specic antihistamines showed minor decreases across
trimesters, as did the antitussive dextromethorphan.
The increase in diphenhydramine use from 1.0% during
the prepregnancy interval to 1.8% in the third trimester
was primarily due to the use of Benadryl.
BDS data reveal secular trends of selected specic
OTC products for a 28-year period (Figure 1). As
aspirin use decreased during the 1980s, acetaminophen
use increased; as acetaminophen use leveled o in the
1990s, ibuprofen use increased after it became available
OTC (1984), followed by an increase in naproxen use
after it became available OTC (1994). Pseudoephedrine
use increased up until the early 1990s, when it stabilized
at prevalences of 15% to 18%. Among antihistamines,
chlorpheniramine use has decreased, while diphenhydramine use has increased. Also, the use of loratadine, a

776
nonsedating antihistamine, increased from 0.2% when
it rst became available by prescription to 3.7% in 2003
after it became available OTC. Both guaifenesin and
dextromethorphan use also increased over the past 2
decades. Ranitidine also increased in use from 0.6% in
1996 to 2000 to 1.6% in 2001 to 2004, after OTC
availability in 1995 (data not presented).
We examined demographic and regional patterns of
OTC medication use in the NBDPS data. In Figure 2,
rates of analgesic, decongestant, and antihistamine use
in pregnancy are presented for categories of maternal
race or ethnicity, years of education, and age. Rates of
analgesic and decongestant use were higher for white
women, women with at least a high school education,
and women who were at least 20 years of age. Antihistamine use showed the same pattern for maternal
education and age, but the rates were similar for white,
black, and Asian American women and lower for
Hispanic women.
We adjusted the rates of medication use by standardizing each state to the racial or ethnic, age, and education distributions of all states combined. Figure 3 shows
adjusted rates of analgesic, decongestant, and antihistamine use by state. Adjustment for these 3 demographic
factors accounted for much of the variability of analgesic and antihistamine use across states, whereas the
adjusted rates for decongestant use showed more variability.

Comment
OTC medication use during pregnancy is extremely
common, as observed in the present ndings and in
several earlier studies in the United States.6-8 Both the
BDS and NBDPS show that approximately two-thirds
of women take acetaminophen and that approximately
1 in 6 women takes a decongestant or ibuprofen during
pregnancy. Although the use of some medications, such
as aspirin and chlorpheniramine, has decreased over the
years, most usage has increased during the past 2
decades; ibuprofen, naproxen, diphenhydramine, dextromethorphan, and loratadine have continued to increase in the most recent years. Further, rates of use for
acetaminophen, pseudoephedrine, chlorpheniramine, diphenhydramine, doxylamine, and guaifenesin in the
rst, second, or third trimester of pregnancy are actually
higher than during the 3 months before pregnancy.
Although such increases in use may be due to actual
increases in upper respiratory symptoms during pregnancy, it is more likely that these changes may reect a
more relaxed attitude regarding the use of OTC drugs in
pregnancy. Indeed, health care providers and Internet
access could be partially responsible for this pattern.
Some health care providers supply lists, both as handouts to their patients and on the Internet to the public,
of medications that they deem to be safe to take during

Werler et al
pregnancy. Interestingly, products that contain acetaminophen (eg, Tylenol), pseudoephedrine (eg, Sudafed),
chlorpheniramine (eg, Dristan), diphenhydramine (eg,
Benadryl), and guaifenesin (eg, Robitussin) often are
included on these lists.9,10 Women might interpret the
receipt of a list of safe medications as an encouragement for use should symptoms occur, whereas before
pregnancy, they might have gone untreated.
The reported use of analgesics, decongestants, and
antihistamines was higher for white, non-Hispanic
women, women with more than a high school education,
and women who were at least 20 years of age. Similar
demographic patterns were observed in 2 separate
studies that were conducted in the eastern United States
in the 1980s.6,7
When these demographic factors were taken into
account, the rates of analgesic and antihistamine use
were similar across the states. For decongestants, the
adjusted rates were lowest for the 3 northeastern states
(Massachusetts, New York, and New Jersey).
For reported use of OTC medication during the rst
trimester, prevalences in the NBDPS are generally
similar to those in a study of women who were delivered
in 1995 and were interviewed within 96 hours of delivery.8 However, the reported uses of some medications
were lower in the third trimester in the NBDPS, possibly
because of the longer interval between pregnancy and
interview. Dierences in data collection methods might
also account for the slightly higher prevalences of
specic OTC products any time in pregnancy in the
BDS rather than in the NBDPS. For example, at the
beginning of the interview, the NBDPS asks questions
about occurrences of cold and u and the medications
taken to treat them, whereas the BDS asks questions
about illnesses and medication use toward the end of the
interview. The reporting of cough, cold, or allergy medications might be more accurate in the NBDPS relative to the BDS because some women may grow weary
of reporting exposures toward the end of the lengthy
interview. Conversely, BDS interviews are conducted
closer to the time of delivery and include more prompts
for specic OTC products. Also, a medication identication booklet is used to help women to identify the
product that was taken in a product line, which results
in, for example, a larger proportion of acetaminophenexposed women reporting the use of a combination product in the BDS (23%) than in the NBPDS (12%). The
enhanced reporting of combination products results
in more exposures to pseudoephedrine, antihistamines,
guaifenesin, and dextromethorphan, which are available
in various combinations with acetaminophen in a single
product.
The potential for inaccurate recall is problematic in
retrospective studies. For OTC medications, accurate
recall can be more dicult because their use during
pregnancy tends to be viewed more casually than does

Werler et al
the use of prescription drugs, the use tends to be of
shorter duration than for prescription products, and the
use tends to be as needed rather than on a particular
schedule, which makes it more dicult to recall the
precise exposure period. Recall of OTC medication use
can be enhanced by prompting in multiple ways within
the interview, such as asking for products by indication
and by product name.11 Women can be asked to retrieve
the medication package if they still have it, so that the
exact name can be recorded.
Many OTC products are marketed according to the
symptoms they treat and frequently contain more than
1 active ingredient (for example, Tylenol PM, Tylenol
Allergy & Sinus, Tylenol Cold and Flu, and Tylenol
Cough, each contain acetaminophen in combination
with various antihistamines, decongestants, and antitussives). One way to help women recall the exact
products that were taken is to ask questions about or
provide pictures of specic products.
Specialized studies are necessary to generate information about the risks and safety of OTC medication
use during pregnancy. Structural birth defects include
many types of malformations that are heterogeneous
with respect to their cause. Because known teratogenic
medications tend to aect the development of specic
types of birth defects rather than birth defects overall, it
is important to assess the use of specic medications in
relation to specic outcomes.12 For example, isotretinoin embryopathy includes certain types of characteristic brain, ear, and heart defects,3 and valproic acid
increases the risk of neural tube defects (NTDs).2 If
OTC medications were high-risk teratogens (like thalidomide or isotretinoin), they would most likely have
come to attention. However, without careful and directed study, it is possible that smaller risks of specic
defects are going undetected. From a public health
perspective, it is useful to compare the impact of a
teratogenic prescription drug with a putative teratogenic
OTC drug. If valproic acid increases the risk of NTDs
approximately 10-fold and 1% of pregnancies are
exposed, the drug would be responsible for an estimated
360 NTD cases in the United States annually. For
comparison, consider a hypothetic OTC drug that is
taken by 20% of women and that increases NTD risk
only 2-fold; although the risk is lower than that of
valproic acid, its far greater prevalence of use would
result in that OTC drug being responsible for approximately 800 NTD cases per year. The common use of
OTC medications in pregnancy necessitates further
studies to establish safety or to identify risks.
In conclusion, because most pregnant women ingest
at least 1 OTC medication, it is imperative that we

777
obtain empiric evidence of whether such exposures are
safe. The methodologic challenges to the study of OTC
medications in pregnancy must be overcome so that the
risks and safety of specic products can be identied,
critical information can be provided to drug manufacturers and public health authorities and, most importantly, both clinicians and women can be allowed to
make more informed treatment decisions. Further, when
risks are identied, that new knowledge can lead to
insights into causal pathways.

Acknowledgments
We thank the Centers for Birth Defects Research and
Prevention in Arkansas, California, Georgia, Iowa,
Massachusetts, New Jersey, New York, and Texas for
their data; Kathy Kelley, Research Pharmacist at Slone
Epidemiology Center, for her assistance with drug
classication; and the mothers who participated in the
BDS or NBDPS.

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