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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
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. N Engl J Med 2009;360:2528-35.
Copyright 2009 Massachusetts Medical Society.

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.

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safety of Metoclopr amide in the First Trimester of Pregnancy

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.

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

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 BeerSheva 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 BeerSheva district and who had a

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, selfreported 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 DemogICD9 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 DemogICD9 record. All diagnoses are classified according to the International Classification of Diseases, 9th revision (ICD9). The three databases one from Clalit Health Services and two from Soroka Medical Center were encoded and linked by personal identifica

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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.
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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 (ICD9 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, selfreported 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

Selfreported 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 medicationadherence rate in two subgroups of our Clalit cohort: women with deepvein throm

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safety of Metoclopr amide in the First Trimester of Pregnancy

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.
Statistical Analysis

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.* Metoclopramide (N = 3458) 27.85.9 924 (26.7) 2534 (73.3) 36 (1.0) 234 (6.8) 22 (0.6) 3.72.7 No Metoclopramide (N = 78,245) 27.96.0 28,307 (36.2) 49,938 (63.8) 2,056 (2.6) 5,128 (6.6) 670 (0.9) 3.72.7 <0.001 0.65 0.20 0.81

Variable Age yr Population group no. (%) Jewish Bedouin Smoking during pregnancy no. (%) Diabetes no. (%) Peripartum fever no. (%) Parity

P Value 0.50 <0.001

The statistical analyses were performed with the use of SPSS software, version 14 (SPSS). Charac teristics of mothers of the exposed group and of mothers of the unexposed group were compared with the use of the chisquare test or Fishers exact test for categorical variables and Students ttest for continuous variables. Linear trend was assessed with the use of the chisquare test for linearity and the BreslowDay test for homogeneity in subgroup analyses. Multivariate logisticregression models were constructed to identify independent risk fac tors associated with adverse outcomes for the fe tus. A categorical multivariate logisticregression 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.

* Plusminus values are means SD. Ethnic group was determined from information in the administrative computerized databases.

Adherence

R e sult s
Study Population

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.
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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Table 2. Odds Ratios for Adverse Outcomes after Intrauterine Exposure to Metoclopramide during the First Trimester, as Compared with Nonexposure. Exposed to Metoclopramide (N = 3458) Not Exposed to Metoclopramide (N = 78,245)

Variable

Odds Ratio (95% CI) Unadjusted Adjusted*

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

* 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 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,
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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).

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 of Metoclopramide* None 17 814 1521 22 Major Congenital Malformations no./total no. (%) 3834/78,245 (4.9) 138/2502 (5.5) 29/674 (4.3) 5/118 (4.2) 10/164 (6.1) 1.00 (reference category) 1.08 (0.911.29) 0.86 (0.591.25) 0.84 (0.342.05) 1.23 (0.652.34) Adjusted Odds Ratio (95% CI)

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 recordlinkage 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 boardcertified 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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* 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.

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 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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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
References
1. Gadsby R, BarnieAdshead AM, Jag

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 ShohamVardi, Department of Epi demiology, BenGurion 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.

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.

ger C. A prospective study of nausea and vomiting during pregnancy. Br J Gen Pract 1993;43:2458. [Erratum, Br J Gen Pract 1993;43:325.] 2. Vellacott ID, Cooke EJ, James CE. Nausea and vomiting in early pregnancy. Int J Gynaecol Obstet 1988;27:5762. 3. Weigel RM, Weigel MM. Nausea and vomiting of early pregnancy and pregnan cy outcome: a metaanalytical review. Br J Obstet Gynaecol 1989;96:13128. 4. Deuchar N. Nausea and vomiting in pregnancy: a review of the problem with particular regard to psychological and so cial aspects. Br J Obstet Gynaecol 1995; 102:68. 5. Lo WY, Friedman JM. Teratogenicity of recently introduced medications in hu man pregnancy. Obstet Gynecol 2002;100: 46573. 6. American College of Obstetrics and Gynecology. ACOG (American College of

Obstetrics and Gynecology) Practice Bul letin: nausea and vomiting of pregnancy. Obstet Gynecol 2004;103:80315. 7. Einarson A, Koren G, Bergman U. Nausea and vomiting in pregnancy: a com parative European study. Eur J Obstet Gy necol Reprod Biol 1998;76:13. 8. Pradalier A, Chabriat H, Danchot J, Baudesson G, Joire JE. Safety and efficacy of combined lysine acetylsalicylate and metoclopramide: repeated intakes in mi graine attacks. Headache 1999;39:12531. 9. Sidhu MS, Lean TH. The use of meto clopramide (Maxolon) in hyperemesis grav idarum. Proc Obstet Gynaecol Soc Singa pore 1970;1:436. 10. Rosa F. Personal communication, FDA 1993. In: Briggs GG, Freeman RK, Yaffe SJ, eds. Drugs in pregnancy and lactation: a reference guide of fetal and neonatal risk. 7th ed. Baltimore: Lippincott Williams & Wilkins, 2005:105761. 11. Berkovitch M, Elbirt D, Addis A,

SchulerFaccini L, Ornoy A. Fetal effects of metoclopramide therapy for nausea and vomiting of pregnancy. N Engl J Med 2000;343:4456. 12. Srensen HT, Nielsen GL, Christens en K, TageJensen U, Ekbom A, Baron J. Birth outcome following maternal use of metoclopramide. Br J Clin Pharmacol 2000; 49:2648. 13. Berkovitch M, Mazzota P, Greenberg R, et al. Metoclopramide for nausea and vom iting of pregnancy: a prospective multi center international study. Am J Perinatol 2002;19:3116. 14. Central Bureau of Statistics. Statisti cal abstract of Israel 2008. No. 59. Popula tion by district, subdistrict and religion. Table 2.6. (Accessed May 15, 2009, at http://www.cbs.gov.il/reader.) 15. Idem. State of Israel: Hodaa laitonut. (Accessed May 15, 2009, at http://www.cbs. gov.il/hodaot2007n/01_07_215b.pdf.) 16. World Health Organization Collabo

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safety of Metoclopr amide in the First Trimester of Pregnancy

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