Introduction

Up to 90% of women experience symptoms of nausea and/or vomiting during pregnancy.1 Hyperemesis gravidarum (HG) is a severe complication of pregnancy affecting around 1% of pregnancies globally.2 HG can cause significant physical and psychological morbidity for mothers.3 The majority of women experiencing severe NVP/HG require one or more medications to assist with symptom control.4 Ondansetron is an effective antiemetic that is being widely used as a second-line treatment option for severe nausea and vomiting of pregnancy (NVP) in accordance with clinical guidelines.5-8
Currently, the increasing use of ondansetron was observed world-wide to treat NVP and HG. In the US, ondansetron use increased from less than 1% of pregnancies before 2001 to as high as 13–25% in 2014, resulting in approximately 500,000 to 1 million ondansetron exposed gestations out of 4 million pregnancies a year.9-11 In Australia and New Zealand, 25 and 75% of physicians prescribed ondansetron for NVP and HG, respectively.12 In Norway, Prescriptions for ondansetron were filled in 0.3% of pregnancies, with 76.9% being initially filled in the first trimester.13 In France, prescriptions of ondansetron only concerned 53 women (0.1%) between 2004 and 2017 in Haute-Garonne, contrary to other countries, like the United States.14
In November 2019, the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) released an updated comprehensive assessment report which state that ondansetron should not be used during the first trimester of pregnancy.15 A review about 0ndansetron in pregnancy revisited do not support the conclusion of EMA/PRAC assessment report and this section of the SmPC, and the regulatory authorities should consider deleting this sentence from the SmPC.16 Indeed, the safety of ondansetron hasn’t concluded a decision now. Some studies did not observe an increased risk of abnormal pregnancy outcome in women who took ondansetron early in pregnancy,17-18 but others reported an increased risk of diaphragmatic hernia, hypoplastic left heart and respiratory system anomalies.19-20 One recent meta-analysis has been published in 2020 which search was conducted by authors until November 2019, so this meta-analysis does not take into account the five latest published studies,21-25 which include three largest ever published studies, including respectively 456,963/33, 677/1,880,594 pregnant women exposed to ondansetron. And three of the five studies focus on not only the risk of malformations, but also other abnormal pregnancy outcome.21-22,25
Therefore, this systematic review and meta-analysis was aim to quantify the association between exposure to ondansetron during pregnancy and the risk of abnormal pregnancy outcomes.