Risk of malformation after Ondansetron in pregnancy: an updated systematic review and meta-analysis

Ondansetron is increasingly used off label to treat nausea and vomiting of pregnancy. The main objective was to evaluate the risk of major congenital malformations (MCM), cardiac defects and orofacial clefts associated with first trimester exposure to ondansetron using a meta-analytic approach. MEDLINE, ClinicalTrials.gov and Scopus were searched until November 2019. All comparative cohort and case-control studies on MCM, cardiac or orofacial defects and use of ondansetron during pregnancy were included. A team of paired reviewers independently extracted data using a proprietary collaborative WEB-based meta-analysis platform (metaPreg.org). Pooled odd ratios with corresponding 95% CIs were calculated using random effects models. From 214 records initially found, 12 studies were included. Using all available information to date, first trimester exposure to ondansetron was found to be associated with an increased risk of i) ventricular septal defects (VSD) (OR 1.11, 95% CI 1.00-1.23; p<0.05; n = 6 studies; I²=0%; p=0.04) and ii) oral clefts (OR 1.22, 95% CI 1.00-1.49; p<0.05; n = 4 studies; I²=0%). No significant association was observed for the risk of cleft palates but, when excluding study that contributed to the study heterogeneity, we found an OR of 1.48 (95% CI 1.19-1.84; p<0.01; n = 5 studies; I²=0%). No statistically significant association was found for MCM, overall cardiac malformations, atrial septal defects and cleft lip with or without cleft palate. Exploratory investigation of other malformations showed an increased risk of diaphragmatic hernia, hypoplastic left heart and “respiratory system anomalies”.