Mirtazapine or ondansetron for hyperemesis gravidarum: a randomized placebo-controlled trial.

Abstract

Hyperemesis gravidarum is a severe pregnancy complication, and ondansetron is recommended as a second-line treatment despite lack of placebo-controlled trials. Case reports suggest that mirtazapine may be more effective, yet it has not been tested in a controlled trial. The aim of this trial was to examine the effect of mirtazapine and ondansetron in hyperemesis gravidarum. The VOMIT (Validating the effect of Ondansetron and Mirtazapine In Treating hyperemesis gravidarum) trial was a randomized double-blind placebo-controlled multicenter trial conducted in 7 hospitals in Denmark 2019 through 2022. Fifty nine pregnant people with hyperemesis gravidarum defined by Pregnancy Unique Quantification of Emesis 24 score ≥13 or Pregnancy Unique Quantification of Emesis 24 score ≥7 if accompanied by weight loss ≥5% or need for hospitalization were included in the trial. Participants were randomly assigned 1:1:1 to oral treatment with mirtazapine, ondansetron, or placebo for an intervention duration of 14 days. The primary outcome was reduction of Pregnancy Unique Quantification of Emesis 24 score on day 2 in intention-to-treat analyses. The trial was registered at Clinicaltrials.gov, NCT03785691. Difference in Pregnancy Unique Quantification of Emesis 24 score change from baseline to day 2 in the mirtazapine (n=21) vs the placebo (n=20) group was -1.86 (95% confidence interval, -3.61 to -0.12; P=.04). In ondansetron (n=18) vs placebo, the difference was -0.51 (95% confidence interval, -2.32 to 1.30), and in mirtazapin vs ondansetron, the difference was -1.35 (95% confidence interval, -3.10 to 0.40). The differences in Pregnancy Unique Quantification of Emesis 24 score change in mirtazapine vs both ondansetron and placebo were more evident after day 4. All analyses regarding symptom severity showed a tendency toward mirtazapine being a more effective treatment than both placebo and ondansetron; however, not all results were significant. The incidence of mild to moderate adverse events was higher with mirtazapine, and serious adverse events were few and evenly distributed. The trial showed reduced Pregnancy Unique Quantification of Emesis 24 score in the mirtazapine group compared with the placebo group among pregnant people with hyperemesis gravidarum. Ondansetron resulted in a smaller reduction in Pregnancy Unique Quantification of Emesis 24 score that did not reach statistical significance.