Original Research

Ondansetron Compared With Doxylamine

and Pyridoxine for Treatment of Nausea
in Pregnancy
A Randomized Controlled Trial
Lauren G. Oliveira, DO, Shannon M. Capp, MD, Whitney B. You, MD, MPH, Robert H. Riffenburgh, PhD,
and Shaun D. Carstairs, MD
OBJECTIVE: To evaluate whether ondansetron or the
combination of doxylamine and pyridoxine was superior
for the treatment of nausea and vomiting of pregnancy.
METHODS: This was a double-blind, randomized, controlled trial in which women with nausea and vomiting of
pregnancy were assigned to 4 mg of ondansetron plus
a placebo tablet or 25 mg pyridoxine plus 12.5 mg of
doxylamine for 5 days. The primary outcome was an
improvement in nausea as reported on a 100-mm visual
analog scale (VAS). Secondary outcomes were a reduction
in vomiting on the VAS and the proportion of patients
reporting sedation or constipation while using either
study regimen.
RESULTS: Thirty-six women (18 in each group) were
randomized to either ondansetron or pyridoxine and doxylamine, of whom 13 (72%) and 17 (94%) completed followup, respectively. There were no differences among the
groups with regard to demographic characteristics or
baseline nausea. Patients randomized to ondansetron were
more likely to have an improvement in their baseline nausea
From the Departments of Emergency Medicine, Obstetrics and Gynecology, and
Clinical Investigation, Naval Medical Center, San Diego, California; and the
Department of Emergency Medicine, Naval Medical Center, Portsmouth,
Virginia.
The views expressed herein are the authors and do not necessarily reflect the
official policy or position of the Department of the Navy, Department of Defense,
or the U.S. Government.
The authors thank Marthile Goldman, RN, for administrative assistance.
Presented at the Society for Academic Emergency Medicine meeting, May 1418,
2013, Atlanta, Georgia.
Corresponding author: Lauren G. Oliveira, DO, 620 John Paul Jones Circle,
Portsmouth, VA 23708; e-mail: Lauren.G.Oliveira@gmail.com.
Financial Disclosure
The authors did not report any potential conflicts of interest.
2014 by The American College of Obstetricians and Gynecologists. Published
by Lippincott Williams & Wilkins.
ISSN: 0029-7844/14

VOL. 124, NO. 4, OCTOBER 2014

as compared with those using pyridoxine and doxylamine

over the course of 5 days of treatment (median VAS score
decreased 51 mm [interquartile range 3764] compared
with 20 mm [851]; P5.019). Furthermore, women using
ondansetron reported less vomiting (median VAS decreased
41 [interquartile range 1757] compared with 17 [24 to 38];
P5.049). There was no significant difference between the
groups regarding sedation or constipation.
CONCLUSION: Our investigation showed ondansetron to
be superior to the combination of pyridoxine and doxylamine in the treatment of nausea and emesis in pregnancy.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.
clinicaltrials.gov, NCT01668069.
(Obstet Gynecol 2014;124:73542)
DOI: 10.1097/AOG.0000000000000479

LEVEL OF EVIDENCE: I

p to 80% of expectant women experience some

degree of nausea and vomiting in pregnancy.1 For
approximately one third of these women, nausea and
vomiting in pregnancy causes a significant clinical, psychological, and economic burden because of missed
work time, increased health care visits, and negative
effects on family relationships.14 Many women with
this condition report increased feelings of depression
and believe it negatively affects their relationship with
their partner.5 Furthermore, nearly 50% of working
pregnant women believe their job efficiency was
reduced and approximately 25% require time off
work.6 Severe nausea and vomiting of pregnancy can
result in dehydration and weight loss that require hospitalization; rare complications include Wernicke
encephalopathy, splenic avulsion, esophageal rupture,
pneumothorax, and acute tubular necrosis.3
Pharmacologic management has been attempted
with a variety of medications with varying success.

OBSTETRICS & GYNECOLOGY

735

Notably, limited data exist to guide the choice of

antiemetic drugs for nausea and vomiting of pregnancy. Although formal evaluation has been limited,
available studies and clinical experience support the
routine use of pyridoxine, metoclopramide, ondansetron, and antihistamines such as doxylamine.13,68
The combination of pyridoxine (vitamin B6) and doxylamine is recommended by the American College of
Obstetricians and Gynecologists as first-line therapy for
nausea and vomiting in pregnancy.9 However, despite
the lack of evidence, the 5-hydroxytryptamine type 3
receptor antagonist ondansetron has become the most
frequently prescribed antiemetic for the treatment of
nausea and vomiting of pregnancy in the United
States.10 The objective of our study was to evaluate
whether ondansetron was superior to the combination
of pyridoxine and doxylamine for the treatment of
nausea and vomiting of pregnancy.

MATERIALS AND METHODS

We performed a double-blind, randomized, controlled trial comparing the efficacy of ondansetron
with the combination of pyridoxine and doxylamine
for the treatment of nausea and vomiting in pregnancy. Patients were enrolled from October 2012
through April 2013 at a tertiary care medical center
that serves beneficiaries of active duty and retired
military personnel. Enrollment occurred in both the
emergency department and the obstetrics and gynecology clinic. This study was approved by the
hospitals Institutional Review Board and was registered at clinicaltrials.gov (NCT01668069).
Eligible women were those requesting treatment
for nausea with or without vomiting associated with
pregnancy who were at least 18 years of age and at
less than 16 weeks of gestation (by last menses or
ultrasonogram). Estimated gestational age was confirmed by ultrasonogram at a later date if not available
on the day of enrollment. Women were excluded
from the study if their nausea or vomiting predated
the pregnancy, hospitalization was required at the
time of initial enrollment, they were already using
anti-emetics (including metoclopramide, ondansetron,
doxylamine, pyridoxine, or promethazine), they had
an allergy to any of the study medications, they were
unable to return for a follow-up visit in 1 week, or
they were unable to obtain the medications on the day
of enrollment. After written informed consent was
obtained, a computer-generated program randomly
allocated participants to either pyridoxine and doxylamine group or ondansetron and placebo group.
Before the start of enrollment, one pharmacist prepared all medications and sealed bottles in identical

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Oliveira et al

numbered brown bags that corresponded to the

patient number. The dispensing pharmacist, treating
provider, patient, and enrolling investigator were
blinded to the medication regimen. Each regimen
consisted of capsules that were identical in appearance. The United States government paid for all study
medications. Patients were not specifically counseled
at time of enrollment or follow-up on dietary changes
or nonpharmacologic methods to remedy nausea.
Before initiating treatment, each patient was
asked to grade the severity of nausea and emesis
experienced over the previous 7 days on two separate
100-mm visual analog scales (VAS) ranging from
0 (indicating no nausea or emesis) to 100 (indicating
worst nausea or emesis imaginable). A VAS was used
because it correlates well with numerical and verbal
descriptors of nausea and has been used in the
oncology, emergency medicine, and anesthesia literature to investigate the efficacy of anti-emetic medications.1113 There are no well-validated tools to
measure nausea or vomiting associated with pregnancy. Previous studies that span a variety of medical
specialties use various criteria to define a clinically
significant improvement in nausea or vomiting with
regard to the VAS. We chose the most conservative of
values (25 mm) to indicate a clinically significant
reduction in nausea and vomiting on the VAS.
The ondansetron group was given one capsule
containing ondansetron 4 mg and one placebo capsule
to be taken orally every 8 hours for 5 days. The
pyridoxine and doxylamine group was given one
capsule containing pyridoxine 25 mg and one capsule
containing doxylamine 12.5 mg to be taken orally every
8 hours for 5 days. Patients were reevaluated 5 to 7 days
after initiating the drug regimen. At this time, the
patients graded the severity of their nausea and emesis
over the treatment period on the VAS. Patients were
also asked if they experienced any adverse effects over
the 5-day treatment period, including constipation,
sedation, headache, an alternative previously unspecified adverse effect, or a combination of these. Age,
estimated gestational age, current medications, gravidity,
and parity were recorded for each patient. At follow-up,
the remaining pills were collected to assess compliance.
Statistical analysis was performed using Stata 13
software. An a priori power calculation indicated that
14 patients per group (28 total) provided 90% power, at
an alpha of 0.05, to detect a 25-mm difference in the
mean improvement on the VAS between the groups
with a standard deviation of 22 mm. To account for
patient attrition, we planned to enroll 18 patients per
group for a total of 36 participants. We planned to
analyze data using the intention-to-treat principle, all

Ondansetron vs Doxylamine and Pyridoxine for Nausea

OBSTETRICS & GYNECOLOGY

Fig. 1. Study recruitment and randomization process.

Oliveira. Ondansetron vs Doxylamine
and Pyridoxine for Nausea. Obstet
Gynecol 2014.

tests were two-sided, and the level of significance was

set at less than .05. Demographic characteristics and the
mean difference on the VAS for nausea and emesis
between each group were compared using the Wilcoxon rank-sum test. The difference in the proportion of
patients who had a clinically significant improvement
(25 or more VAS units) in their nausea or vomiting was
assessed using the Fisher exact test. Finally, the
difference in the proportion of patients who experienced side effects in each group was compared using
the Fisher exact test. Five patients were lost to follow-up
and the initial data for one patient were not available at
the time of the final analysis. The influence of missing
data on the results was assessed as follows. Missing data
were estimated by multiple imputation over variables
by group that had missing data. The imputation was an
iterative Markov chain Monte Carlo method using 100
imputations, each of which consisted of 1,000 simulations on a multivariate Normal regression, using the
variables with missing data as predictors. Descriptive
statistics of variables with missing data without and with
imputed values were consistent, differing only negligibly, and t-test results were far from significant. The
rank-sum and Fisher exact tests were repeated with
imputed data included and the results were tabulated.

RESULTS
Forty eligible patients were approached for enrollment and four patients declined participation. A total

VOL. 124, NO. 4, OCTOBER 2014

Oliveira et al

of 36 women were enrolled and randomized to

treatment, with 30 fully completing the study (13 in
the ondansetron group, 17 in the pyridoxine and
doxylamine group) (Fig. 1). Five patients were lost to
follow-up: one from the pyridoxine and doxylamine
group and four from the ondansetron group. Additionally, the pretreatment nausea and emesis VAS
were unavailable for review at the time of final analysis for one patient in the ondansetron group, so her
data were excluded. Baseline characteristics for each
group are reported in Table 1. No significant differences between the groups were observed with regard
to demographics (gravidity, parity, or estimated gestational age) or level of nausea or vomiting before
treatment. There was no difference in demographics
in the patients who were lost to follow-up.
Table 1. Baseline Demographic Characteristics and
Initial Visual Analog Scale Scores by
Group
Demographic
Gravid
Parity
Gestational age (wk)
Baseline nausea (mm)
Baseline emesis (mm)

Ondansetron
2
1
8
73
53

(13)
(01)
(7.18.9)
(6784)
(2674)

Pyridoxine and
Doxylamine
2
0.5
8.1
81
64

(13)
(01)
(7.29.9)
(6893)
(2689)

Data are median (interquartile range).

Ondansetron vs Doxylamine and Pyridoxine for Nausea

737

Table 2. Change in Visual Analog Scale Score for Ondansetron and Pyridoxine and Doxylamine Groups
From Missing Data DB
Variable
Change in nausea
Change in emesis

Group
Ondansetron
Pyridoxine and doxylamine
Ondansetron
Pyridoxine and doxylamine

Median (IQR)
51
20
41
17

(3764)
(851)
(1757)
(24 to 38)

P
.019
.049

From Imputed Data DB

Median (IQR)
45
19
46
12

(2762)
(849)
(2267)
(29 to 37)

P
.037
.010

DB, database; IQR, interquartile range.

P values for rank-sum tests between ondansetron and pyridoxine and doxylamine groups for database with missing values and database with
imputed values. All were significant at .05.

The primary outcome was the reduction in

nausea on the VAS. Patients using ondansetron
reported a greater reduction in nausea than those
using pyridoxine and doxylamine (median 51 mm
[interquartile range 3764] compared with 20 mm
[interquartile range 851]; P5.019) (Table 2 and
Fig. 2). Additionally, those who were using ondansetron reported less vomiting on the VAS as compared
with the pyridoxine and doxylamine group (median 41
[interquartile range 1757] compared with 17 [interquartile range 24 to 38]; P5.049) (Table 2 and Fig. 2).
In the ondansetron group, 12 out of the 13 patients
had a clinically significant reduction in nausea (defined
as a 25-mm or greater reduction in nausea on the VAS);
however, in the pyridoxine and doxylamine group,
only 7 out of 17 patients had a clinically significant

reduction (P5.007) (Table 3 and Fig. 3). In the ondansetron group, 10 out of the 13 patients had a reduction
in emesis on the VAS; however, in the pyridoxine and
doxylamine group, only 6 out of 17 patients had
a reduction in emesis (P5.033) (Table 3 and Fig. 4).
This study was adequately powered to detect only
differences in the primary outcome and we found no
differences between the groups with respect to sedation
or constipation. Four patients in the ondansetron group
and seven patients in the pyridoxine and doxylamine
group reported sedation (P5.707), whereas five patients in the ondansetron group and three patients in
the pyridoxine and doxylamine group reported constipation (P5.412). Additionally, in the ondansetron
group, one patient reported headache, one patient reported dry mouth, one patient reported pruritis, and

Fig. 2. The median reduction in nausea and vomiting on the visual analog scale (mm) for each medication regimen. CI,
confidence interval.
Oliveira. Ondansetron vs Doxylamine and Pyridoxine for Nausea. Obstet Gynecol 2014.

738

Oliveira et al

Ondansetron vs Doxylamine and Pyridoxine for Nausea

OBSTETRICS & GYNECOLOGY

Table 3. Clinically Significant Improvements

From Missing Data DB
Test
Change in nausea
Change in emesis

Group

n/N (%)

Ondansetron
Pyridoxine and doxylamine
Ondansetron
Pyridoxine and doxylamine

12/13
7/17
10/13
6/17

(92.3)
(41.2)
(76.9)
(35.3)

P
.007
.033

From Imputed Data DB

P

n/N (%)
15/18
7/18
13/18
6/18

(83.3)
(38.9)
(72.2)
(33.3)

.015
.044

DB, database; VAS, visual analog scale.

Significant change (25 VAS mm or more) for groups with associated Fisher exact test P compared for missing data database and imputed data
database.

one patient reported increased salivation. At follow-up,

one patient was admitted for reasons unrelated to her
nausea in pregnancy. There were no unexpected
adverse events in either treatment group.
Compliance was similar between groups; both
had a mean of 7 out of 30 pills remaining at follow-up
(P5.906). No patient included in the final analysis
returned for additional medications or treatments
before follow-up.
The five patients lost to follow-up were tracked in
our electronic medical record. Four patients were
from the ondansetron group and one patient was from

the pyridoxine and doxylamine group. Three were

not prescribed any additional medication and
improved on follow-up visits. One patient in ondansetron group reported improved symptoms and was
given additional ondansetron 6 days after enrollment.
One patient in the ondansetron group reported no
change in symptoms and was given ondansetron and
pyridoxine 4 days after enrollment.
We investigated the sensitivity of our results to
missing data by imputing the absent data and rerunning the statistical tests as described in Materials
and Methods. Significance in VAS reduction

Fig. 3. Change in nausea on the visual analog scale (mm) for each patient. A reduction of at least 25 mm on the visual
analog scale is considered clinically significant.
Oliveira. Ondansetron vs Doxylamine and Pyridoxine for Nausea. Obstet Gynecol 2014.

VOL. 124, NO. 4, OCTOBER 2014

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Ondansetron vs Doxylamine and Pyridoxine for Nausea

739

Fig. 4. Change in emesis on the visual analog scale (mm) for each patient. A reduction of at least 25 mm on the visual
analog scale is considered clinically significant.
Oliveira. Ondansetron vs Doxylamine and Pyridoxine for Nausea. Obstet Gynecol 2014.

decreased 1.8% in the test of difference between

groups for change in nausea attributable to treatment
(P increased to .037) (Fig. 5) and increased 3.9% for
change in emesis (P decreased to .010) (Table 2,

Fig. 6). Significance in clinical improvement decreased

0.8% on the test of difference between groups for
a change in nausea attributable to treatment
(P increased to .015) and decreased 1.1% for a change

Fig. 5. Pretreatment and posttreatment visual analog scale (mm) for

nausea for each individual patient
for (A) ondansetron and (B) pyridoxine and doxylamine.
Oliveira. Ondansetron vs Doxylamine
and Pyridoxine for Nausea. Obstet
Gynecol 2014.

740

Oliveira et al

Ondansetron vs Doxylamine and Pyridoxine for Nausea

OBSTETRICS & GYNECOLOGY

Fig. 6. Pretreatment and posttreatment visual analog scale (mm) for

emesis for each individual patient
for (A) ondanstetron and (B) pyridoxine and doxylamine.
Oliveira. Ondansetron vs Doxylamine
and Pyridoxine for Nausea. Obstet
Gynecol 2014.

in emesis (P increased to .044) (Table 3). Because

changes were not large and occurred in both directions, and because all tests remained significant, we
concluded that the missing data did not represent
a major consistent bias.

DISCUSSION
Two randomized controlled trials showed that pyridoxine alone significantly reduced the severity of
nausea and vomiting in pregnancy symptoms in
women with moderate or severe nausea and vomiting
when compared with placebo.8,14 The combination of
pyridoxine and doxylamine (an antihistamine that
blocks H1 receptors), known as Bendectin in the
United States, was widely prescribed to women with
nausea and vomiting in pregnancy from 1958 to
1983.6 When the manufacturer voluntarily removed
the drug from the market because of false allegations
regarding teratogenic effects, there was a twofold to
threefold increase in the rate of hospitalization because
of nausea and vomiting in pregnancy.6 Importantly,
the safety of the combination of doxylamine and
pyridoxine since has been demonstrated in more than
200,000 first-trimester exposures.7 Meta-analyses
report that use of pyridoxine and doxylamine during
pregnancy is not associated with an increased incidence of birth defects.15,16 Finally, a case-control investigation from the Northern California Kaiser
Permanente Birth Defects Study concluded no causal
association between Bendectin use and birth defects.
Both pyridoxine and doxylamine are U.S. Food and
Drug Administration (FDA) Pregnancy Safety Class A,

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Oliveira et al

and the combination has been associated with a 70%

reduction in nausea and vomiting.9 Recently, the FDA
approved the combination of pyridoxine and doxylamine for the treatment of nausea and vomiting of
pregnancy under the trade name Dicelgis.
Many pharmacologic therapies that are prescribed
in the context of pregnancy are not specifically approved
for use in a gravid population. Although ondansetron
does not have FDA indication for treatment of nausea
and vomiting of pregnancy, it is commonly used in
practice. Nonpregnant patients have shown dramatic
responses to this antiemetic, with up to 50% reduction in
vomiting when compared with conventional treatments,
which has led to prescribing ondansetron during pregnancy.1,17,18 A comparative study of patients with hyperemesis gravidarum suggested ondansetron and
promethazine had similar efficacy; however, ondansetron was less sedating.16 Three case reports to date
describe the use of ondansetron for nausea and vomiting
of pregnancy because of failed conventional treatment of
hyperemesis gravidarum.1719 Although currently FDA
Pregnancy Safety Class B, Pasternak et al recently reported that in a cohort of 608,385 pregnancies, receipt
of ondansetron was not associated with a significantly
increased risk of spontaneous abortion, stillbirth, major
birth defects, preterm delivery, or delivery of a lowbirth-weight neonate.11,20 Although another study using
the same database reported an association between filling a prescription for ondansetron and heart defects in
the offspring, these data have only been presented in
abstract form and cannot be used to establish causation.
The FDA recently warned about the potential for QT

Ondansetron vs Doxylamine and Pyridoxine for Nausea

741

prolongation with the 32-mg intravenous dosing of

ondansetron; however, the recommended oral dosing
was not changed.21 Certainly, this must be considered
before prescribing ondansetron and treatment for any
patient must be individualized based on their medical
history and concurrent medication profile.
The average wholesale price (base cost) of the
study medications is $0.13 for 12.5 mg of doxylamine,
$0.03 for 25 mg of pyridoxine, and $1.35 for 4 mg of
ondansetron (generic), all in tablet form.22 Whether
ondansetron would be cost-beneficial or cost-effective
for the treatment of nausea and vomiting of pregnancy
requires formal analysis and was beyond the scope of
this study.
A limitation to this study is that there is no known
standard or validated tool for quantifying nausea or
vomiting in the context of pregnancy. We used the
VAS that has been used in the anesthesia and
emergency medicine literature, and we extrapolated
its use to a pregnant population. Another possible
limitation to this study is that it was conducted at
a single center treating primarily military members and
their beneficiaries. Military hospitals offer free care and
medications, which may increase the treatmentseeking. Also, although none of the patients required
hospitalization for nausea during pregnancy during the
trial period, our study was not powered to detect
a difference between the need for hospitalization, time
out of work, or improved mood between groups.
In conclusion, our investigation showed ondansetron to be superior to the combination of pyridoxine
and doxylamine in the treatment of nausea during
pregnancy. Although our sample was quite small, the
strength of outcome differences suggests that it might
well be considered as a possible first-line therapy.
Decreasing the incidence of nausea during pregnancy
will likely improve the mental and physical health of
patients, allowing less time away from work, resulting
in less health care expenditures on urgent visits, and
increasing quality of life.
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