Hyperemesis gravidarum causes severe dehydration, weight loss, and maternal morbidity, yet evidence guiding second-line pharmacotherapy remains scarce. In the multicenter double-blind randomized placebo-controlled VOMIT trial across seven Danish hospitals, pregnant individuals with hyperemesis gravidarum were randomized 1:1:1 to oral mirtazapine, ondansetron, or placebo for 14 days. At day 2, mirtazapine produced a statistically significant reduction in the Pregnancy-Unique Quantification of Emesis 24 score versus placebo (mean difference -1.86; 95% CI -3.61 to -0.12; P = .04), whereas ondansetron led to a smaller, non-significant reduction (-0.51; 95% CI -2.32 to 1.30).

Mild-to-moderate adverse events were more frequent with mirtazapine, but serious adverse events were rare and balanced across arms. Overall, mirtazapine demonstrated prompt symptom alleviation, positioning it as an…