Aetiology Cohort study
Metoclopramide in pregnancy: no association with adverse fetal and neonatal outcomes 10.1136/eb-2013-101654
Ilan Matok, Amichai Perlman Faculty of Medicine, Division of Clinical Pharmacy, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel Correspondence to: Dr Ilan Matok, Division of Clinical Pharmacy, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, PO Box 12065, Jerusalem 9112001, Israel; [email protected]
and stillbirths, and secondary analysis comparing spontaneous abortion between exposure to metoclopramide and to antihistamine antiemetics.
Findings There was no increase in major congenital malformations among women exposed to metoclopramide in the first trimester (25.3 cases/1000 births, 95% CI 23.5 to 27.1) compared with non-exposed women (26.6 cases/ 1000 births, 95% CI 25.7 to 27.5). There were no significant associations between metoclopramide use and the risk for congenital malformations overall (adjusted prevalence OR=0.93, 95% CI 0.86 to 1.02) or with any of the 20 individual malformation categories examined. Metoclopramide was not associated with increased risk of spontaneous abortion (20 cases/ 1000, 95% CI 18.5 to 21.4) versus non-exposed women (62.1 cases/1000, 95% CI 60.9 to 63.3); or stillbirth (3.5 cases/1000, 95% CI 2.9 to 4.1, vs 3.9 cases/1000, 95% CI 3.6 to 4.2). There were also no significant associations between metoclopramide exposure and preterm birth (OR=0.98, 95% CI 0.93 to 1.05), low birth weight (OR=0.98, 95% CI 0.92 to 1.05) or SGA (OR=1.00, 95% CI 0.96 to 1.04).
Commentary Commentary on: Pasternak B, Svanström H, Mølgaard-Nielsen D, et al. Metoclopramide in pregnancy and risk of major congenital malformations and fetal death. JAMA 2013;310:1601–11.
Context Nausea and vomiting of pregnancy (NVP) affects as many as 50–80% of pregnant women during the first trimester.1 NVP can cause considerable physical and psychological distress, can often be debilitating and sometimes requires hospitalisation. In addition to rehydration and various dietary recommendations, treatment of NVP often requires pharmacological interventions, such as an antihistamine combined with pyridoxine, 5-HT3 antagonist or dopamine antagonist. Despite their widespread use, data regarding the safety of many of these agents in pregnancy are limited, due to the exclusion of pregnant women from clinical trials on ethical grounds. This retrospective cohort study assessed the safety of metoclopramide in pregnancy, examining the incidence of congenital malformations, spontaneous abortions and stillbirth in women exposed to metoclopramide during pregnancy, compared with those unexposed.
Methods This was a register-based cohort study, including all pregnancies in Denmark from 1997 to 2011. Metoclopramide-exposed and unexposed women were matched (1–4 ratio) on the basis of age, calendar year and propensity scores. Pregnancy, fetal and neonatal outcomes included major congenital malformations diagnosed within the first year of life, spontaneous abortion, stillbirth, preterm birth, low birth weight and small for gestational age (SGA). Exposure to metoclopramide and its timing were defined according to data from the Danish National Prescription Registry, with appropriate exposure windows defined for each of the outcomes. Sensitivity analyses included adjustment for the number of prescriptions, subgroup analysis of malformation cases among induced abortions
This large cohort study is an important and reassuring addition to the existing body of literature regarding the safety of exposure to metoclopramide during pregnancy.2–4 Previously published cohort and case– control studies involving metoclopramide have found no evidence of increased risk for adverse pregnancy, fetal or neonatal outcomes. However, the majority of these studies were of limited size, with the largest including 3458 exposed pregnancies,2 and were therefore only powered to detect relatively large differences in relative risk. The current study is an important contribution in this regard, providing data from over 28 000 pregnancies with exposure to metoclopramide. In addition to reproducing the results of previous studies, this study was sufficiently powered to rule out a twofold increase in the relative risk for 17 individual major malformations. However, results indicating an inverse association between metoclopramide exposure and spontaneous abortion should be viewed with caution. The authors largely attribute this finding to the documented protective association NVP itself has with regard to spontaneous abortion. Correction notice This article has been corrected since it was published Online First. The last sentence has been amended and reference 5 deleted. Competing interests None. References 1. Lacroix R, Eason E, Melzack R. Nausea and vomiting during pregnancy: a prospective study of its frequency, intensity, and patterns of change. Am J Obstet Gynecol 2000;182:931–7. 2. 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. 3. Berkovitch M, Elbirt D, Addis A, et al. Fetal effects of metoclopramide therapy for nausea and vomiting of pregnancy. N Engl J Med 2000;343:445–6. 4. Berkovitch M, Mazzota P, Greenberg R, et al. Metoclopramide for nausea and vomiting of pregnancy: a prospective multicenter international study. Am J Perinatol 2002;19:311–16.
Evid Based Med June 2014 | volume 19 | number 3 |
115
Metoclopramide in pregnancy: no association with adverse fetal and neonatal outcomes 10.1136/eb-2013-101654
Ilan Matok, Amichai Perlman Faculty of Medicine, Division of Clinical Pharmacy, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel Correspondence to: Dr Ilan Matok, Division of Clinical Pharmacy, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, PO Box 12065, Jerusalem 9112001, Israel; [email protected]
and stillbirths, and secondary analysis comparing spontaneous abortion between exposure to metoclopramide and to antihistamine antiemetics.
Findings There was no increase in major congenital malformations among women exposed to metoclopramide in the first trimester (25.3 cases/1000 births, 95% CI 23.5 to 27.1) compared with non-exposed women (26.6 cases/ 1000 births, 95% CI 25.7 to 27.5). There were no significant associations between metoclopramide use and the risk for congenital malformations overall (adjusted prevalence OR=0.93, 95% CI 0.86 to 1.02) or with any of the 20 individual malformation categories examined. Metoclopramide was not associated with increased risk of spontaneous abortion (20 cases/ 1000, 95% CI 18.5 to 21.4) versus non-exposed women (62.1 cases/1000, 95% CI 60.9 to 63.3); or stillbirth (3.5 cases/1000, 95% CI 2.9 to 4.1, vs 3.9 cases/1000, 95% CI 3.6 to 4.2). There were also no significant associations between metoclopramide exposure and preterm birth (OR=0.98, 95% CI 0.93 to 1.05), low birth weight (OR=0.98, 95% CI 0.92 to 1.05) or SGA (OR=1.00, 95% CI 0.96 to 1.04).
Commentary Commentary on: Pasternak B, Svanström H, Mølgaard-Nielsen D, et al. Metoclopramide in pregnancy and risk of major congenital malformations and fetal death. JAMA 2013;310:1601–11.
Context Nausea and vomiting of pregnancy (NVP) affects as many as 50–80% of pregnant women during the first trimester.1 NVP can cause considerable physical and psychological distress, can often be debilitating and sometimes requires hospitalisation. In addition to rehydration and various dietary recommendations, treatment of NVP often requires pharmacological interventions, such as an antihistamine combined with pyridoxine, 5-HT3 antagonist or dopamine antagonist. Despite their widespread use, data regarding the safety of many of these agents in pregnancy are limited, due to the exclusion of pregnant women from clinical trials on ethical grounds. This retrospective cohort study assessed the safety of metoclopramide in pregnancy, examining the incidence of congenital malformations, spontaneous abortions and stillbirth in women exposed to metoclopramide during pregnancy, compared with those unexposed.
Methods This was a register-based cohort study, including all pregnancies in Denmark from 1997 to 2011. Metoclopramide-exposed and unexposed women were matched (1–4 ratio) on the basis of age, calendar year and propensity scores. Pregnancy, fetal and neonatal outcomes included major congenital malformations diagnosed within the first year of life, spontaneous abortion, stillbirth, preterm birth, low birth weight and small for gestational age (SGA). Exposure to metoclopramide and its timing were defined according to data from the Danish National Prescription Registry, with appropriate exposure windows defined for each of the outcomes. Sensitivity analyses included adjustment for the number of prescriptions, subgroup analysis of malformation cases among induced abortions
This large cohort study is an important and reassuring addition to the existing body of literature regarding the safety of exposure to metoclopramide during pregnancy.2–4 Previously published cohort and case– control studies involving metoclopramide have found no evidence of increased risk for adverse pregnancy, fetal or neonatal outcomes. However, the majority of these studies were of limited size, with the largest including 3458 exposed pregnancies,2 and were therefore only powered to detect relatively large differences in relative risk. The current study is an important contribution in this regard, providing data from over 28 000 pregnancies with exposure to metoclopramide. In addition to reproducing the results of previous studies, this study was sufficiently powered to rule out a twofold increase in the relative risk for 17 individual major malformations. However, results indicating an inverse association between metoclopramide exposure and spontaneous abortion should be viewed with caution. The authors largely attribute this finding to the documented protective association NVP itself has with regard to spontaneous abortion. Correction notice This article has been corrected since it was published Online First. The last sentence has been amended and reference 5 deleted. Competing interests None. References 1. Lacroix R, Eason E, Melzack R. Nausea and vomiting during pregnancy: a prospective study of its frequency, intensity, and patterns of change. Am J Obstet Gynecol 2000;182:931–7. 2. 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. 3. Berkovitch M, Elbirt D, Addis A, et al. Fetal effects of metoclopramide therapy for nausea and vomiting of pregnancy. N Engl J Med 2000;343:445–6. 4. Berkovitch M, Mazzota P, Greenberg R, et al. Metoclopramide for nausea and vomiting of pregnancy: a prospective multicenter international study. Am J Perinatol 2002;19:311–16.
Evid Based Med June 2014 | volume 19 | number 3 |
115
