The n e w e ng l a n d j o u r na l of
original article
From the Departments of Epidemiology
and Health Services Evaluation (I.M., A.L.),
Pediatrics (R.G.), and Obstetrics and Gy-
necology (E.S., A.W.), Faculty of Health
Sciences, Ben-Gurion University of the
Negev; Soroka Medical Center (R.G., E.S.,
A.W.), Clalit Health Services (Southern
District) (R.G., A.W.), and the BeMORE
Collaboration (R.G., A.L.) all in Beer-
Sheva, Israel; the Motherisk Program,
Division of Clinical Pharmacology, Hos-
pital for Sick Children, University of To-
ronto, and the BeMORE Collaboration,
Toronto (G.K.); and the Department of
Medicine, University of Western Ontario,
London, Canada (G.K.). Address reprint
requests to Dr. Gorodischer at the Soroka
Medical Center, P.O. Box 151, Beer-Sheva
84101, Israel, or at rafaelg@bgu.ac.il.
N Engl J Med 2009;360:2528-35.
Copyright 2009 Massachusetts Medical Society.
2528
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m e dic i n e
The Safety of Metoclopramide Use
in the First Trimester of Pregnancy
Ilan Matok, M.Sc.Pharm., Rafael Gorodischer, M.D., Gideon Koren, M.D.,
Eyal Sheiner, M.D., Ph.D., Arnon Wiznitzer, M.D., and Amalia Levy, M.P.H., Ph.D.
A bs t r ac t
Background
In various countries, metoclopramide is the antiemetic drug of choice in pregnant
women, but insufficient information exists regarding its safety in pregnancy.
Methods
We investigated the safety of metoclopramide use during the first trimester of preg
nancy by linking a computerized database of medications dispensed between Janu
ary 1, 1998, and March 31, 2007, to all women registered in the Clalit Health Ser
vices, southern district of Israel, with computerized databases containing maternal
and infant hospital records from the district hospital during the same period. We
assessed associations between the use of metoclopramide in pregnancy and adverse
outcomes for the fetus, adjusting for parity, maternal age, ethnic group, presence
or absence of maternal diabetes, smoking status, and presence or absence of peri
partum fever.
Results
There were 113,612 singleton births during the study period. A total of 81,703 of
the infants (71.9%) were born to women registered in Clalit Health Services; 3458
of them (4.2%) were exposed to metoclopramide during the first trimester of preg
nancy. Exposure to metoclopramide, as compared with no exposure to the drug, was
not associated with significantly increased risks of major congenital malformations
(5.3% and 4.9%, respectively; odds ratio, 1.04; 95% confidence interval [CI], 0.89 to
1.21), low birth weight (8.5% and 8.3%; odds ratio, 1.01; 95% CI, 0.89 to 1.14), pre
term delivery (6.3% and 5.9%; odds ratio, 1.15; 95% CI, 0.99 to 1.34), or perinatal
death (1.5% and 2.2%; odds ratio, 0.87; 95% CI, 0.55 to 1.38). The results were mate
rially unchanged when therapeutic abortions of exposed and unexposed fetuses were
included in the analysis.
Conclusions
In this large cohort of infants, exposure to metoclopramide in the first trimester was
not associated with significantly increased risks of any of several adverse outcomes.
These findings provide reassurance regarding the safety of metoclopramide for the
fetus when the drug is given to women to relieve nausea and vomiting during preg
nancy.
n engl j med 360;24 nejm.org june 11, 2009
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Copyright 2009 Massachusetts Medical Society. All rights reserved.
 safety of Metoclopr amide in the First Trimester of Pregnancy
A
s many as 50 to 80% of pregnant
women have nausea and vomiting during
the first trimester. These symptoms may
be severe and can continue beyond the first trimes
ter.1-4 Pregnant women and health professionals
often refrain from pharmacologic treatment of
morning sickness owing to fears of teratogenic
effects.1-4 In the case of more than 90% of the
drugs approved by the Food and Drug Adminis
tration in the past 20 years, there are insufficient
data from human studies to determine whether the
benefits of therapy exceed the risk to the fetus.5
In the United States and Canada, the drugs of
choice for the treatment of nausea and vomiting
during pregnancy are pyridoxine and doxylamine,
whereas metoclopramide is used only in the most
severe cases.6 Although the label for metoclopra
mide does not include the indications of nausea
and vomiting during pregnancy, metoclopramide
is the antiemetic drug of choice in some European
countries and in Israel.7 There is extensive experi
ence with the use of this medication in nonpreg
nant persons, with evidence of overall low rates of
adverse events when it is used as recommended.8
Despite its extensive use, only a few studies
have assessed the safety to the fetus of maternal
exposure to metoclopramide during the first tri
mester,9-13 and the relatively small sizes of these
studies limited their power to detect adverse ef
fects of the drug. We designed the present study
to investigate, in a large cohort of pregnant wom
en, the safety for the fetus of exposure to meto
clopramide during the first trimester.
Me thods
Study Population
We performed a retrospective cohort study involv
ing members of Clalit Health Services, the largest
health maintenance organization in Israel. Clalit
Health Services insures 70% of the population 15
to 49 years of age in the Beer-Sheva district in
southern Israel; the district had 565,200 inhabit
ants in 2006.14 Soroka Medical Center is the re
gional hospital, at which 98% of deliveries in the
district take place; it is estimated that the same
proportion of women enrolled in Clalit Health Ser
vices deliver at Soroka Medical Center.15
All girls and women 15 to 49 years of age who
were registered in Clalit Health Services and were
living in the Beer-Sheva district and who had a
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singleton delivery at Soroka Medical Center were
included in the analyses. The study period ex
tended from January 1, 1998, through March 31,
2007. Approximately half of the infants in the dis
trict are born to Jewish parents, and half to Bed
ouin Muslim parents.
Databases
The clinical, medication, and demographic data
related to members of Clalit Health Services are
aggregated in a Clalit Health Services database and
can be accessed at the level of an individual mem
ber. The medication data in the database include
information about the date on which drugs were
dispensed, the Anatomical Therapeutic Chemical
(ATC) classification codes of the drugs (including
the commercial and generic names), the dose
schedules, and the dose dispensed in terms of the
defined daily dose (i.e., the assumed average main
tenance dose per day).
Two computerized databases at Soroka Medical
Center, which draw information directly from
original sources, were used. All patients records
at Soroka Medical Center originate from a single
database, which includes demographic informa
tion and hospitalization dates recorded at the time
of the womans admission to the hospital and at
the time of the infants birth. The Obstetrics and
Gynecology Department database includes infor
mation on maternal health status during preg
nancy and delivery, maternal age, gestational age
at delivery (the number of days since the last men
strual period), perinatal death, parity, ethnic group,
self-reported smoking status during pregnancy,
and infant birth weight and Apgar score at 1 and
5 minutes. The diagnoses are reviewed routinely
by a trained medical secretary before entry into the
database.
The other electronic database at Soroka Medi
cal Center that was used in the present study was
the Demog-ICD9 database, which includes demo
graphic and medical diagnoses during hospitaliza
tion, with medical diagnoses drawn directly from
the medical records. Additional diagnoses related
to the infant at discharge are coded and included
in the infants Demog-ICD9 record. All diagnoses
are classified according to the International Classifi-
cation of Diseases, 9th revision (ICD-9).
The three databases one from Clalit Health
Services and two from Soroka Medical Center
were encoded and linked by personal identifica
2529
 The n e w e ng l a n d j o u r na l
tion numbers (numbers that are given at birth by
the Interior Ministry and used throughout life) to
create a registry of medications dispensed during
pregnancy and of pregnancy outcomes.
The study was approved by the local institu
tional ethics committee in accordance with the
principles of the Declaration of Helsinki. In accor
dance with Ministry of Health regulations, the
institutional ethics committee did not require writ
ten informed consent because the data were ob
tained anonymously from medical files, with no
participation of patients.
Study Design
The exposed group comprised the infants of wom
en to whom metoclopramide (ATC code A03FA01)
was dispensed during the first trimester of preg
nancy (at 13 weeks gestation or earlier). The first
day of the last menstrual period was defined as
the first day of gestation. Use of metoclopramide
was also classified in terms of the total number
of defined daily doses dispensed; the defined daily
dose of metoclopramide is 30 mg.16 In Israel, all
metoclopramide formulations contain 10 mg of
metoclopramide in each tablet, and the drug is usu
ally prescribed for 7 days at a dose of 30 mg per
day. We divided the total defined daily doses dis
pensed into the following categories: 1 to 7, 8 to
14, 15 to 21, and 22 or more. For example, 7 de
fined daily doses would be a total of 21 metoclopra
mide tablets of 10 mg each taken either as 30 mg
per day for 7 days or as a total of 210 mg taken
over the course of the first trimester. The unex
posed group comprised the infants of all women
who did not take metoclopramide during the first
trimester over the course of the study period. We
performed a secondary analysis of data from in
fants whose mothers refilled their prescriptions
at least once.
Data on outcomes with respect to the infants
were ascertained from the hospital records of each
mother and newborn, which had the same unique
number for the hospitalization. The Soroka Med
ical Center databases were linked by this single
hospitalization number. The mothers and infants
personal identification numbers were also used
for linking data. Data on therapeutic abortions
were manually collected from the registry of the
Committee for Termination of Pregnancies at So
roka Medical Center, encoded, and linked to the
Soroka and Clalit databases with the use of the
encoded womans personal identification number.
2530 n engl j med 360;24 nejm.org june 11, 2009
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of m e dic i n e
The following outcomes were investigated for
both live neonates and stillborns: major and minor
malformations, clusters (i.e., similar malforma
tions in more than one infant) and multiple con
genital malformations (i.e., more than one mal
formation in one infant), subclasses of major
congenital malformations, perinatal death, pre
term birth (birth at a gestational age of <37
weeks), low birth weight (<2500 g), very low birth
weight (<1500 g), and Apgar score at 1 minute
and 5 minutes after birth (Apgar 7 or 8). A sub
group analysis was performed to compare the
outcome for infants of women who received meto
clopramide and refilled the prescription at least
once with the outcome in the unexposed group.
We used the definitions of major and minor
congenital malformations that were developed by
the Metropolitan Atlanta Congenital Defects Pro
gram of the Centers for Disease Control and Pre
vention (CDC).17-19 Chromosomal diseases were
excluded. In subclass analyses of major malforma
tions, the following specific defects were exam
ined: anencephaly (ICD-9 code, 740); spina bifida
(741); other anomaly of the nervous system (742);
anomalies of the eye (743); anomalies of the ear,
face and neck (744); bulbus cordis anomalies and
anomalies of cardiac septal closure (745); other
anomalies of the heart (746); other anomalies of
the circulatory system (747); anomalies of the re
spiratory system (748); cleft palate and lip (749);
other anomalies of the upper alimentary tract
(750); other anomalies of the digestive system
(751); genital anomalies (752); anomalies of the
urinary system (753); musculoskeletal deformities
(754); other anomalies of the limbs (755); other
musculoskeletal anomalies (756); and anomalies
of the integument (757).
The following potential confounders were in
cluded in the statistical analysis: maternal age,
parity, self-reported smoking status during preg
nancy, presence or absence of maternal diabetes
mellitus, presence or absence of peripartum fever
(defined as a temperature of 38C or higher), and
ethnic group (i.e., Jewish or Bedouin Muslim).
Adherence
Self-reported information to confirm the use of
metoclopramide was not available. In an attempt
to estimate the rate of adherence to prescribed drug
treatment in this cohort more generally, we looked
at the medication-adherence rate in two subgroups
of our Clalit cohort: women with deep-vein throm
 safety of Metoclopr amide in the First Trimester of Pregnancy

bosis during their pregnancy for whom enoxaparin

Table 1. Characteristics of Women to Whom Metoclopramide Was Dispensed
had been prescribed20 and women with familial in the First Trimester of Pregnancy and of Women to Whom It Was Not
Mediterranean fever for whom colchicine had been Dispensed.*
prescribed.21 We compared the information re
No
garding enoxaparin and colchicine, respectively, Metoclopramide Metoclopramide
in the dispensed-medications database of Clalit Variable (N=3458) (N=78,245) P Value
Health Services with each mothers report of the Age yr 27.85.9 27.96.0 0.50
medication use as it appeared in her hospital ob Population group no. (%)
stetrical medical record.
Jewish 924 (26.7) 28,307 (36.2) <0.001

Statistical Analysis Bedouin 2534 (73.3) 49,938 (63.8)

The statistical analyses were performed with the Smoking during pregnancy 36 (1.0) 2,056 (2.6) <0.001
no. (%)
use of SPSS software, version 14 (SPSS). Charac
teristics of mothers of the exposed group and of Diabetes no. (%) 234 (6.8) 5,128 (6.6) 0.65
mothers of the unexposed group were compared Peripartum fever no. (%) 22 (0.6) 670 (0.9) 0.20
with the use of the chi-square test or Fishers exact Parity 3.72.7 3.72.7 0.81
test for categorical variables and Students t-test
for continuous variables. Linear trend was assessed * Plusminus values are means SD.
Ethnic group was determined from information in the administrative comput-
with the use of the chi-square test for linearity and erized databases.
the BreslowDay test for homogeneity in subgroup
analyses. Multivariate logistic-regression models
were constructed to identify independent risk fac Adherence
tors associated with adverse outcomes for the fe We assessed rates of adherence to pharmacologic
tus. A categorical multivariate logistic-regression treatment in two subgroups of the cohort by com
model was constructed to determine whether paring self-reported medication use with medica
greater exposure was associated with an increased tion dispensed according to the pharmacy data
risk of major congenital malformations. Odd ra base. The adherence rate was 93% among 66
tios and their 95% confidence intervals were com women with deep-vein thrombosis for whom enox
puted. aparin had been prescribed and 96% among 43
women with familial Mediterranean fever for
R e sult s whom colchicine had been prescribed.

Study Population Outcomes

There were 113,612 singleton births at Soroka
Medical Center during the study period; 81,703
(71.9%) of the infants were born to mothers who
were registered in Clalit Health Services. Of those,
3458 (4.2%) were exposed to metoclopramide dur
ing the first trimester of pregnancy. During the
study period, there were 998 therapeutic pregnan
cy terminations at Soroka Medical Center among
women registered at Clalit Health Services (records
of 8 women, or 0.8%, could not be linked owing
to incorrect identification numbers); 38 of the 998
women had received metoclopramide during the
first trimester.
Characteristics of mothers and infants who
were exposed to metoclopramide and of mothers
and infants who were not exposed to the drug are
summarized in Tables 1 and 2, respectively. The
mean (SD) exposure to metoclopramide during
the first trimester was 7.25.4 defined daily doses.
A total of 4016 infants (4.9%) were identified as
having one or more major congenital malforma
tions (3.9% of Jewish infants and 5.5% of Bed
ouin infants). There were 1761 perinatal deaths;
a major congenital malformation was diagnosed
in 173 (9.8%) of these infants.
The rate of major congenital malformations
identified in the group that was exposed to meto
clopramide during the first trimester was 5.3%
(182 of 3458 infants), as compared with a rate of
4.9% (3834 of 78,245 infants) in the unexposed
group (crude odds ratio, 1.10; 95% confidence in
terval [CI], 0.93 to 1.26; adjusted odds ratio, 1.04;
95% CI, 0.89 to 1.21) (Table 2). No significant as
sociation was found when pregnancy terminations
were included in the analysis (6.1% [213 infants]
in the exposed group and 5.9% [4679 infants] in
the unexposed group; adjusted odds ratio, 0.99;
95% CI, 0.86 to 1.14). Similarly, exposure to meto

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 2. Odds Ratios for Adverse Outcomes after Intrauterine Exposure to Metoclopramide during the First Trimester,
as Compared with Nonexposure.

Exposed to Not Exposed to

Metoclopramide Metoclopramide
Variable (N=3458) (N=78,245) Odds Ratio (95% CI)
Unadjusted Adjusted*
no. (%)
Congenital malformations
Major 182 (5.3) 3834 (4.9) 1.10 (0.931.26) 1.04 (0.891.21)
Minor 133 (3.8) 2730 (3.5) 1.11 (0.931.32) 1.10 (0.921.31)
Preterm birth (<37 wk) 219 (6.3) 4593 (5.9) 1.08 (0.941.25) 1.15 (0.991.34)
Perinatal death 53 (1.5) 1708 (2.2) 0.70 (0.530.92) 0.87 (0.551.38)
Birth weight
Low (<2500 g) 295 (8.5) 6497 (8.3) 1.03 (0.911.16) 1.01 (0.891.14)
Very low (<1500 g) 59 (1.7) 1115 (1.4) 1.20 (0.921.56) 1.18 (0.901.54)
Apgar score 7
At 1 min 188 (5.6) 4149 (5.5) 1.02 (0.871.18) 0.97 (0.841.13)
At 5 min 28 (0.8) 708 (0.9) 0.88 (0.611.29) 0.84 (0.571.22)

* The odds ratios for all outcomes except major and minor congenital malformations were adjusted for maternal age,
ethnic group, presence or absence of maternal diabetes, maternal smoking status, presence or absence of peripartum
fever, and parity. For major and minor congenital malformations, the odds ratios were adjusted for maternal age, eth-
nic group, presence or absence of maternal diabetes, maternal smoking status, and parity.
Owing to missing data on Apgar scores at 1 minute for some infants, the percentages were calculated on the basis of
3357 infants in the exposed group and 75,133 in the unexposed group.

clopramide during the first trimester of preg
nancy was not significantly associated with an
increased risk of minor congenital malformations
(Table 2) or of multiple malformations (2.5% [85
infants] and 2.3% [1832 infants] in the exposed
and unexposed groups, respectively; adjusted odds
ratio, 0.92; 95% CI, 0.70 to 1.21). No significant
associations were found between subclasses of
major congenital malformations and exposure to
metoclopramide during the first trimester of preg
nancy (see Table 1 in the Supplementary Appen
dix, available with the full text of this article at
NEJM.org). In addition, no unexpected cluster of
anomalies was observed in infants exposed to
metoclopramide during the first trimester of preg
nancy.
In subgroup analyses stratified according to
ethnic group, metoclopramide was not signifi
cantly associated with an increased rate of major
congenital malformations in Jews (adjusted odds
ratio, 1.08; 95% CI, 0.78 to 1.49) or in Bedouins
(odds ratio, 1.02; 95% CI, 0.86 to 1.22; P=0.93 for
the test of homogeneity). Exposure to metoclopra
mide was also not associated with significantly
increased risks of preterm birth, low Apgar scores,
or perinatal death (Table 2). Similarly, no differ
ences between the exposed and unexposed groups
were found in the rates of low birth weight or very
low birth weight (Table 2).
There was no significant doseresponse effect
in the association between metoclopramide and
the risk of major congenital malformations (Table
3). In unadjusted analyses, the frequency of major
congenital malformations in the group exposed
to 22 or more defined daily doses (6.1%) appeared
to be greater than the frequency in the groups
with less exposure (5.5%, 4.3%, and 4.2% in the
groups that were exposed to 1 to 7, 8 to 14, and 15
to 21 defined daily doses, respectively) and greater
than the frequency in the unexposed group (4.9%),
but there was no significant trend according to
the defined daily doses either in the univariate
analysis (P=0.55 for trend) or in the analysis ad
justed for maternal age, ethnic group, presence
or absence of maternal diabetes, maternal smok
ing status, and parity (P=0.82 for trend in mul
tivariate analysis).
In addition, 758 of the 3458 mothers (21.7%)
refilled their prescription for metoclopramide at
least once. The rate of major congenital malfor

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 safety of Metoclopr amide in the First Trimester of Pregnancy
mations among infants born to these mothers was
3.8% (29 infants), as compared with 4.9% (3834
infants) in the unexposed group (adjusted odds
ratio, 0.76; 95% CI, 0.53 to 1.11).
Discussion
Metoclopramide has been extensively used for de
cades to treat nausea and vomiting in pregnant
women, despite a lack of data on the safety of the
drug in pregnancy. In this large, population-
based cohort, we found no significant associa
tion between metoclopramide treatment in the
first trimester and adverse outcomes for the fetus,
including congenital malformations, perinatal
death, low birth weight, and low Apgar scores.
Until now, the assumption that the use of
metoclopramide in pregnancy is not associated
with congenital malformations has been based on
studies with small samples, totaling 800 pregnan
cies: a record-linkage study,10 a retrospective con
trol study,12 and two prospective observational
studies.11,13 Our findings are consistent with the
results of those studies. The absence of a signifi
cant association in our study between exposure to
metoclopramide during the first trimester and
low birth weight, very low birth weight, and pre
term birth is also consistent with the findings in
most of the previous, smaller studies.12,13,22
Soroka Medical Center is a district hospital
where practically all deliveries in the region take
place; all infants are examined after birth in the
Neonatology Department, under the supervision
of board-certified neonatologists. This may ex
plain the higher rate of detection of congenital
malformations in the current study than in pre
vious studies. Higher rates of congenital malfor
mations have been documented among Bedouins
than among Jews, a finding that is possibly attrib
utable to increased rates of consanguinity among
Bedouins.23,24
A strength of our study, in contrast to previ
ous studies,10-13 was the availability of information
on the metoclopramide dose. Despite the large
size of our study, the fact that the duration of ex
posure averaged about 1 week means that the
number of fetuses who were actually exposed dur
ing any particular period that is critical for em
bryonic development was much smaller than the
total number of exposed fetuses. Nonetheless, our
study addresses the typical exposure of the fetus
to metoclopramide among women who have nau
sea and vomiting associated with pregnancy.
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Table 3. Odds Ratios for Major Congenital Malformations Associated
with Exposure to Metoclopramide during the First Trimester of Pregnancy,
According to Levels of Defined Daily Doses.
Total Defined Daily Doses Major Congenital Adjusted Odds Ratio
of Metoclopramide* Malformations (95% CI)
no./total no. (%)
None 3834/78,245 (4.9) 1.00 (reference category)
17 138/2502 (5.5) 1.08 (0.911.29)
814 29/674 (4.3) 0.86 (0.591.25)
1521 5/118 (4.2) 0.84 (0.342.05)
22 10/164 (6.1) 1.23 (0.652.34)
* The defined daily dose is the assumed average maintenance dose per day for
a drug when it is used in adults for its main indication; the defined daily dose
of metoclopramide is 30 mg,16 usually dispensed in 10-mg tablets. Thus, 7 de-
fined daily doses would be a total of 21 tablets of 10 mg each taken either as
30 mg per day for 7 days or as a total of 210 mg taken over the course of the
first trimester.
Odds ratios were adjusted for maternal age, ethnic group, presence or ab-
sence of maternal diabetes, maternal smoking status, and parity.
A limitation of our report is the possibility that
some outcomes may have been misclassified, be
cause the classification of outcomes was based on
administrative data rather than on a review of
medical records. Several studies have used multi
center administrative or provincial databases, with
variations in coding of medical diagnoses across
and within databases.25,26 In contrast, we obtained
diagnostic information from databases of a single
hospital, which drew data only from the medical
record; diagnoses of congenital malformations
were made under the supervision of neonatologists
who were experts in the field of congenital mal
formations. The accuracy of the databases used
in this study is further supported by the observed
inverse association between smoking and the use
of metoclopramide, a finding that has been re
ported previously.27 High estrogen levels are one
of the suspected causes of nausea and vomiting
during pregnancy, and maternal smoking has been
linked to reduced estrogen levels.27
The databases used in our study contained in
formation regarding metoclopramide that was
dispensed to pregnant women, but data on the
degree of adherence to metoclopramide therapy
were not available. We found that rates of medi
cation adherence were more than 90% in two
subgroups of our cohort (women with deep-vein
thrombosis and women with familial Mediterra
nean fever), but it is unclear whether these high
adherence rates would be generalizable to wom
en with nausea and vomiting during pregnancy.
A recent study that used the same database at
2533
 The n e w e ng l a n d j o u r na l of m e dic i n e

Clalit Health Services showed that the overall ad
herence to iron supplements dispensed for Israeli
infants was high, as confirmed by laboratory
tests.28 Previous studies have shown that comput
erized pharmacy records provide accurate medi
cation data and have high rates of concordance
with medication use reported by patients in gen
eral29-31 and by pregnant women specifically.32
Nevertheless, it is possible that more doses of
metoclopramide were prescribed and dispensed
than were ingested. The observation that the out
comes were similar between the one fifth of
women who refilled their prescription of meto
clopramide at least once and the total cohort
provides further evidence of the safety of the
medication in pregnancy.
Like most published studies of pregnancy out
comes after exposure to a drug, our study does not
include data on spontaneous abortions. However,
a study that included such data did not show a
significant association between exposure to meto
clopramide during the first trimester and the
risk of spontaneous abortion.13
Given the observational design of our study,
we cannot exclude the possibility of confounding.
It is likely that women who took metoclopramide
had more nausea and vomiting during pregnan
cy than did women who did not take the drug.
A significant association has been reported be
tween nausea and vomiting during pregnancy and
more favorable pregnancy outcomes33; this asso
ciation might potentially mask some adverse ef
fects of metoclopramide. However, we attempted
to reduce possible confounding by excluding twin
pregnancies and pregnancies in which the fetus
had Downs syndrome. Twin pregnancies are as
sociated with increased risks of nausea and vom
iting as compared with singleton pregnancies27,34
(potentially increasing the likelihood that meto
clopramide would be prescribed) and are indepen
dently associated with increased risks of low birth
weight, preterm delivery, and congenital malfor
mations. Similarly, a pregnancy in which the fetus
has Downs syndrome is associated with a reduced
risk of nausea and vomiting during pregnancy but
an increased risk of congenital malformations, as
compared with a pregnancy in which the fetus
does not have Downs syndrome; inclusion of these
pregnancies could have led to an underestimation
of the risk associated with metoclopramide.
In summary, this large cohort study shows that
exposure to metoclopramide in the first trimes
ter of pregnancy is not associated with signifi
cantly increased risks of congenital malforma
tions, low birth weight, or perinatal death. These
data provide reassurance about the safety of meto
clopramide use for nausea and vomiting associ
ated with pregnancy.
Dr. Koren reports receiving consulting and lecture fees and
grant support from Duchesnay. No other potential conflict of
interest relevant to this article was reported.
We thank Professor Ilana Shoham-Vardi, Department of Epi
demiology, Ben-Gurion University; Dr. Daniela Landau, Depart
ment of Neonatology, Soroka Medical Center; and members of
the computer units of Clalit Southern District and Soroka Medi
cal Center.

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