Doxylamine-pyridoxine for nausea and vomiting of pregnancy randomized placebo controlled trial: Prespecified analyses and reanalysis

Abstract

Background: Doxylamine-pyridoxine is recommended as a first line treatment for nausea and vomiting during pregnancy and it is commonly prescribed. We re-analysed the findings of a previously reported superiority trial of doxylamine-pyridoxine for the treatment of nausea and vomiting during pregnancy using the clinical study report obtained from Health Canada.

Methods and findings: We re-analysed individual level data for a parallel arm randomized controlled trial that was conducted in six outpatient obstetrical practices in the United States. Pregnant women between 7 and 14 weeks of gestation with moderate nausea and vomiting of pregnancy symptoms. The active treatment was a tablet containing both doxylamine 10 mg and pyridoxine 10 mg taken between 2 and 4 times per day for 14 days depending on symptoms. The control was an identical placebo tablet taken using the same instructions. The primary outcome measure was improvement in nausea and vomiting of symptoms scores using the 13-point pregnancy unique quantification of emesis scale between baseline and 14 days using an ANCOVA. 140 participants were randomized into each group. Data for 131 active treatment participants and 125 control participants were analysed. On the final day of the trial, 101 active treatment participants and 86 control participants provided primary outcome measures. There was greater improvement in symptoms scores with doxylamine-pyridoxine compared with placebo (0.73 points; 95% CI 0.21 to 1.25) when last observation carried forward imputation was used for missing data but the difference is not statistically significant using other approaches to missing data (e.g. 0.38; 95% CI -0.08 to 0.84 using complete data).

Conclusions: There is a trend towards efficacy for nausea and vomiting symptoms with doxylamine-pyridoxine compared with placebo but the statistical significance of the difference depends on the method of handling missing data and the magnitude of the difference suggests that there is no clinically important benefit employing the prespecified minimal clinically important difference or "expected difference" of 3 points.

Trial registration: Clinical Trial NCT00614445.

Conflict of interest statement

Competing Interests: Dr El Emam reports personal fees from Privacy Analytics, outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development, or marketed products to declare.

Figures

Fig 1. CONSORT flow diagram for “ITT-Efficacy” group based on clinical study report (page 6687).

Fig 2. Mean symptom scores on each study day using available cases.

Fig 3. Mean symptom scores on each study day using last observation carried forward imputation.