The use of metoclopramide during pregnancy was not associated with any increased risk of major congenital malformations, spontaneous abortion, stillbirth, preterm birth, low birth weight, or fetal growth restriction in a study assessing 10 times as many exposed pregnancies as all previous cohort studies of this issue combined.
This registry-based cohort study assessed 1,222,503 pregnancies throughout Denmark from 1997 through 2011, including 45,002 (3.7%) in which the mother took metoclopramide, presumably to treat nausea or vomiting. It examined 20 different categories of congenital malformation, said Dr. Björn Pasternak and his associates of the Statens Serum Institut, Copenhagen.
"The number of included pregnancies in our study permitted analyses with precise estimation of risk for most outcomes and allowed analyses of serious adverse outcomes that are rare," the authors noted in a report online Oct. 15 in JAMA.
Dr. Björn Pasternak
The findings confirm and significantly extend those of previously published cohort studies of metoclopramide taken during pregnancy, which included only 4,261 exposed pregnancies in total.
Dr. Pasternak and his colleagues first assessed major congenital malformations in 28,486 liveborn infants exposed to metoclopramide during the first trimester and 113,698 infants who were not exposed and who were matched for age, year of birth, and propensity score. The rate of any major malformation was 25.3 per 1,000 among the exposed infants and 26.6 per 1,000 among the unexposed infants, a nonsignificant difference.
They then analyzed 20 individual categories of congenital malformation, such as neural tube defects, hydronephrosis, ventricular or atrial septal defects, hypospadias, clubfoot, or cleft lip. There were no significant associations between metoclopramide and any type of malformation.
The researchers also assessed 10,171 cases of spontaneous abortion that occurred among 37,946 metoclopramide-exposed pregnancies and 151,661 matched unexposed pregnancies. The rate of spontaneous abortion was slightly lower in exposed than in unexposed pregnancies.
This finding was "not unexpected" because the drug is given to treat nausea and vomiting, conditions that are known to correlate with lower rates of spontaneous abortion in the general population. "Indeed, the strength of the association between nausea and vomiting and spontaneous abortion in previous studies was similar in magnitude to the association between metoclopramide exposure and spontaneous abortion observed in our study," Dr. Pasternak and his associates reported (JAMA 2013;310:1601-11).
They also found that the rate of stillbirth among 40,306 metoclopramide-exposed pregnancies (3.5 per 1,000) was not significantly different from that among 161,098 matched unexposed pregnancies (3.9 per 1,000). So the drug did not raise the risk of stillbirth.
Further analyses showed that metoclopramide exposure was not associated with any of the secondary outcomes of preterm birth, low birth weight, or small-for-gestational-age infants.
The investigators also performed several sensitivity analyses, all of which yielded results similar to those of the primary analyses. For example, the rates of all adverse outcomes were not significantly different between women who filled only one prescription for the drug and those who filled multiple prescriptions, indicating that there was no dose-response effect.
They also assessed a possible exposure effect among pregnancies that were terminated because of major fetal malformations. Again, there was no evidence of an increased risk of malformations overall or of particular types of malformations after exposure to metoclopramide.
These findings "may help inform clinical decisions when treatment with metoclopramide is considered in pregnancy," Dr. Pasternak and his associates said.
This study was supported by the Danish Medical Research Council. No financial conflicts of interest were reported.