Etiology

Metoclopramide during pregnancy did not increase risk for major congenital malformations or fetal death

Pasternak B, Svanström H, Mølgaard-Nielsen D, Melbye M, Hviid A. Metoclopramide in pregnancy and risk of major congenital malformations and fetal death. JAMA. 2013;310:1601-11.

Clinical impact ratings: F ★★★★★★✩ g ★★★★★✩✩ Question Does use of metoclopramide during pregnancy increase risk for major congenital malformations or fetal death?

Methods Design: Retrospective population-based cohort study with individual-level linkage of several national registers. Setting: Denmark. Patients: 1 222 503 singleton pregnancies (mean maternal age 29 y at pregnancy onset) with date of spontaneous abortion or delivery between January 1997 and March 2011. Pregnancies exposed to metoclopramide were matched 1:4 based on age, calendar year, and propensity scores (and, for fetal death analyses, first day of metoclopramide exposure) with pregnancies that were not exposed to metoclopramide during the exposure window. Fetuses/infants with < 6 completed weeks of gestation, missing or implausible gestational ages, chromosomal aberrations, genetic syndromes, malformations with known causes, viral infections possibly associated with malformations, or whose mothers had cancer within 6 months before pregnancy or filled prescriptions for metoclopramide in the month before pregnancy were excluded. Risk factors: Filled prescriptions for maternal use of metoclopramide during pregnancy. Outcomes: Major congenital malformations, spontaneous abortion, and stillbirth. Secondary outcomes included preterm birth (< 37 wk gestational age), low birthweight (< 2500 g), and small-forgestational age (lowest 10th percentile of gestational age–specific birthweight).

adverse outcomes (Table). First-trimester metoclopramide use was not associated with any of 20 specific malformations.

Conclusion Use of metoclopramide during pregnancy did not increase risk for major congenital malformations or fetal death. Source of funding: Danish Medical Research Council. For correspondence: Dr. B. Pasternak, Statens Serum Institut, Copenhagen, Denmark. E-mail [email protected]. ■

Commentary Metoclopramide is prescribed in pregnancy most commonly for nausea and vomiting of pregnancy (NVP). NVP affects up to 90% of pregnancies, with symptoms beginning in the first trimester in 99% of cases, and causes substantial distress in about one third of affected women. Management of NVP can be overly conservative due to the reluctance of affected women to take, and of doctors to prescribe, antiemetic drugs, in large part because of fetal safety concerns. Inadequate symptom control may lead to hyperemesis gravidarum, for which inpatient treatment is usually required. The study by Pasternak and colleagues showed that exposure to metoclopramide (occurring in 3% to 4% of the study population) during early pregnancy seems to be safe, a finding consistent with a previous smaller study (1). The study methodology was appropriate and included statistical adjustment to control for potential confounders. The large sample size allowed for specific powered evaluation of 20 of the most common malformations. The study ruled out an absolute increase of > 0.5 cases of malformations per 1000 exposed infants.

Main results

It is well-established that NVP is associated with a reduced miscarriage rate, a finding supported by this study. Although not significant, the congenital malformation rate seemed to be lower, rather than higher, in women exposed to metoclopramide. The above observations provide a plausible foundation for the idea that significant NVP that requires metoclopramide is associated with a “healthy” concepAssociation between maternal use of metoclopramide during pregnancy and risk for tion, with a negative association between adverse events* symptom severity and adverse pregnancy Outcomes Exposure window Events/1000 pregnancies (n) Adjusted HR/OR outcome. Not addressed in this study was during pregnancy (95% CI)† whether metoclopramide use at high doses Metoclopramide No metoclopramide and for periods > 3 months may be associated Major congenital To 12 wk 25 (28 486) 27 (113 698) OR 0.93 (0.86 to 1.02) with tardive dyskinesia. Overall, the study malformations provides further reassurance on the short-term Spontaneous abortion 7 to 22 wk 20 (37 946) 62 (151 661) HR 0.35 (0.33 to 0.38) use of metoclopramide in early pregnancy.

45 002 fetuses/infants were exposed to a median of 40 doses of metoclopramide, beginning at a median of 57 gestational days. Results show that metoclopramide use during any exposure window during pregnancy did not increase risk for corresponding

Stillbirth

7 wk to birth

Preterm birth

Until 37 wk

3.5 (40 306)

3.9 (161 098)

HR 0.90 (0.74 to 1.08)

50 (36 839)

49 (146 908)

OR 0.98 (0.93 to 1.04)

Low birthweight

Any time

35 (36 864)

34 (147 016)

OR 0.98 (0.92 to 1.05)

Small-for-gestational age

Any time

100 (36 864)

98 (147 016)

OR 1.00 (0.96 to 1.04)

*HR = hazard ratio; OR = odds ratio. CI defined in Glossary. †Adjusted for hospitalization for hyperemesis gravidarum, or nausea and vomiting and use of other antiemetics in exposure window.

18 February 2014 | ACP Journal Club | Volume 160 • Number 4 Downloaded From: http://annals.org/ by a University of Manitoba User on 02/17/2015

Peng Chiong Tan, MD University of Malaya Kuala Lumpur, Malaysia Reference 1. Matok I, Gorodischer R, Koren G, et al. The safety of metoclopramide use in the first trimester of pregnancy. N Engl J Med. 2009;360:2528−35.

© 2014 American College of Physicians

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ACP Journal Club. Metoclopramide during pregnancy did not increase risk for major congenital malformations or fetal death.

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