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n e w e ng l a n d j o u r na l
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original article
A bs t r ac t
Background
From the Departments of Epidemiology
and Health Services Evaluation (I.M., A.L.),
Pediatrics (R.G.), and Obstetrics and Gynecology (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 BeerSheva, Israel; the Motherisk Program,
Division of Clinical Pharmacology, Hospital for Sick Children, University of Toronto, 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.
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.
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
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.
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Me thods
Study Population
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Variable
Metoclopramide
(N=3458)
No
Metoclopramide
(N=78,245)
P Value
Age yr
27.85.9
27.96.0
0.50
<0.001
924 (26.7)
28,307 (36.2)
2534 (73.3)
49,938 (63.8)
36 (1.0)
2,056 (2.6)
<0.001
234 (6.8)
5,128 (6.6)
0.65
22 (0.6)
670 (0.9)
0.20
Parity
3.72.7
3.72.7
0.81
Bedouin
Statistical Analysis
R e sult s
Adherence
Study Population
Outcomes
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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)
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)
* 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.
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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, populationbased 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.
Major Congenital
Malformations
None
3834/78,245 (4.9)
17
138/2502 (5.5)
1.08 (0.911.29)
814
29/674 (4.3)
0.86 (0.591.25)
5/118 (4.2)
0.84 (0.342.05)
10/164 (6.1)
1.23 (0.652.34)
1521
22
* 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 defined 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 absence of maternal diabetes, maternal smoking status, and parity.
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References
1. Gadsby R, Barnie-Adshead AM, Jag
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