sa fe t y of Me t ocl opr a mide in the Fir s t Tr imes ter of Pr egna

nc y

bosis during their pregnancy for whom

enoxaparin had been prescribed20 and women
with familial Mediterranean fever for whom
colchicine had been prescribed.21 We compared
the information re garding enoxaparin and
colchicine, respectively, in the dispensedmedications database of Clalit Health Services
with each mothers report of the medication use
as it appeared in her hospital ob stetrical
medical record.

Table 1. Characteristics of Women to Whom Metoclopramide Was Dispensed

in the First Trimester of Pregnancy and of Women to Whom It Was Not
Dispensed.*

Variable
Age yr

27.85.9

27.96.0

0.50

924 (26.7)

28,307 (36.2)

<0.001

2534 (73.3)

49,938 (63.8)

Population group no. (%)

Jewish
Bedouin

Statistical Analysis

No
Metoclopramide
(N = 78,245)
P Value

Metoclopramide
(N = 3458)

36 (1.0)
2,056 (2.6)
<0.001
The statistical analyses were performed with the Smoking during pregnancy
no. (%)
use of SPSS software, version 14 (SPSS).
234 (6.8)
5,128 (6.6)
0.65
Charac teristics of mothers of the exposed group Diabetes no. (%)
and of mothers of the unexposed group were Peripartum fever no. (%)
22 (0.6)
670 (0.9)
0.20
compared with the use of the chisquare test or Parity
3.72.7
3.72.7
0.81
Fishers exact test for categorical variables and
Students ttest for continuous variables. Linear * Plusminus values are means SD.
Ethnic group was determined from information in the administrative computtrend was assessed with the use of the chisquare erized
databases.
test for linearity and
the BreslowDay test for homogeneity in subgroup
analyses. Multivariate logisticregression models
were constructed to identify independent risk the drug are summarized in Tables 1 and 2, respectively. The
fac tors associated with adverse outcomes for mean (SD) exposure to metoclopramide during the first
the fe tus. A categorical multivariate logistic- trimester was 7.25.4 defined daily doses.
regression model
was constructed
to
determine
whether greater exposure was
associated with an increased risk of major
congenital malformations. Odd ra tios and their
95% confidence intervals were com puted.

Result
s
Study Population

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 f irst 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 f irst
trimester.
Characteristics of mothers and infants who
were exposed to metoclopramide and of
mothers and infants who were not exposed to
n engl j med 360;24

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2531

A
d
h
e
r
e
n
c
e

sa fe t y of Me t ocl opr a mide in the Fir s t Tr imes ter of Pr egna

nc y
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

We assessed rates of adherence

to pharmacologic treatment in
two subgroups of the cohort by
com
paring
selfreported
medication use with medica
tion dispensed according to the
pharmacy data base.
The
adherence
rate was 93%
among 66 women with deepvein thrombosis for whom
enox
aparin
had
been
prescribed and 96% among 43
women
with
familial
Mediterranean fever for whom
colchicine had been prescribed.
O
u
t
c
o
m
e
s

A total of 4016 infants (4.9%)

were identif ied 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
n engl j med 360;24

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2531

T he

n e w e n g l an d j o u r n al

of

m e d ic i n e

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

Variable

Exposed to
Metoclopramide
(N = 3458)

Not Exposed to
Metoclopramide
(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)

219 (6.3)

4593 (5.9)

1.08 (0.941.25)

1.15 (0.991.34)

53 (1.5)

1708 (2.2)

0.70 (0.530.92)

0.87 (0.551.38)

295 (8.5)

6497 (8.3)

1.03 (0.911.16)

1.01 (0.891.14)

59 (1.7)

1115 (1.4)

1.20 (0.921.56)

1.18 (0.901.54)

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)

Preterm birth (<37 wk)

Perinatal death
Birth weight
Low (<2500 g)
Very low (<1500 g)
Apgar score 7

* 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, ethnic 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 f irst trimester of

preg nancy was not signif icantly 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 signif icant
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 stratif ied according to
ethnic group, metoclopramide was not signif i
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 signif icant trend according to the
def ined 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%)
ref illed their prescription for metoclopramide
at least once. The rate of major congenital

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malfor
2532

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sa fe t y of Me t ocl opr a mide in the Fir s t Tr imes ter of Pr egna

nc y

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).

Di s c u s s i o n
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 signif
icant associa tion between metoclopramide
treatment in the f irst 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 recordlinkage
study,10 a retrospective con trol study,12 and
two prospective observational studies.11,13 Our
f indings are consistent with the results of those
studies. The absence of a signifi cant
association in our study between exposure to
metoclopramide during the f irst trimester
and low birth weight, very low birth weight, and
pre term birth is also consistent with the f
indings 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 boardcertif ied 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.

Table 3. Odds Ratios for Major Congenital Malformations Associated

with Exposure to Metoclopramide during the First Trimester of Pregnancy,
sa fe t y of Me t ocl opr a mide in the
Fir s t toTr
imesofter
of Daily
Pr egna
According
Levels
Defined
Doses.

nc y

* 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
n engl j med 360;24

across and within databases.25,26 In contrast, we

Total Defined Daily Doses
Major Congenital
Adjusted Odds Ratio
obtained
diagnostic information
from databases
of Metoclopramide*
Malformations
(95% CI)
of a single hospital, which drew data only from
no./total of
no. (%)
the medical record; diagnoses
congenital
None
3834/78,245
1.00 (reference category)
malformations were made under the (4.9)
supervision
17
138/2502
(5.5)
of neonatologists who were experts in the f ield1.08 (0.911.29)
29/674
0.86 (0.591.25)
of814
congenital mal formations.
The(4.3)
accuracy of
the
databases used in this5/118
study
1521
(4.2)is further
0.84 (0.342.05)
supported
by the observed 10/164
inverse
association1.23 (0.652.34)
22
(6.1)
between
smoking
and
the
use
of
metoclopramide, a f inding 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
deepvein 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

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2533