Antiemetic Use during Pregnancy and Child Neurodevelopmental Disorders: A Nationwide Birth Cohort Study

초록

Background: Antiemetics are commonly prescribed to treat nausea and vomiting during pregnancy (NVP), which occurs in up to 80% of pregnant women. However, data on their long-term neurodevelopmental effects are limited. Objectives: To assess the risk of neurodevelopmental disorders and delays in children exposed to antiemetics commonly prescribed during pregnancy. Methods: This nationwide cohort study, designed to emulated a pragmatic trial, used South Korea's National Health Insurance Service mother-child linked database, 2009–2023. Children born to mothers diagnosed with NVP between 2010 and 2021 were included. The primary exposure of interest was metoclopramide, while pyridoxine, doxylamine, dimenhydrinate, domperidone, and ondansetron were included in secondary analyses. The outcomes included seven neurodevelopmental disorders—autism spectrum disorder, cerebral palsy, communication disorder, intellectual disorder, movement disorder, attention deficit hyperactivity disorder (ADHD), and epilepsy—as well as neurodevelopmental delays assessed annually across six domains by parents using the validated Korean Developmental Screening Test. Children were followed-up until outcome occurrence, death, or the end of the study period. Additionally, interval censoring was applied for neurodevelopmental delay outcomes. Overlap weights based on potential confounders were applied to a Cox proportional hazard model to estimate hazard ratios (HR) with 95% confidence intervals (CI). Results: Among 631,034 children included, 281,476 children (44.6%) were exposed to metoclopramide during pregnancy, while 131,837 (20.9%), 1,383 (0.2%), 12,013 (1.9%), 14,531 (2.3%), and 5,673 (0.9%) were respectively exposed to pyridoxine, doxylamine, dimenhydrinate, domperidone, and ondansetron. There was no substantial association between antiemetic exposure during pregnancy and neurodevelopmental disorders and delays. Findings were consistent across various subgroup and sensitivity analyses, except for a slightly elevated risk of ADHD (HR 1.12, 95% CI 1.06–1.18) in children exposed to metoclopramide during the second half of pregnancy and neurodevelopmental delays in those exposed to metoclopramide for seven or more days. Conclusions: This large-scale study found no association between antiemetic exposure during pregnancy and the risk of neurodevelopmental disorders or delays in children, providing reassurance for the use of antiemetics in pregnancy to treat nausea and vomiting. However, the slightly elevated risks observed in certain subgroups warrant further investigation. Meanwhile, these findings may assist in guiding decisions when considering antiemetic treatment during pregnancy.