Utilization and Adverse Outcomes of Ondansetron and Fluconazole Therapy during Pregnancy

Application Number
17_005
Lay Summary

This study will examine the safety of the use of two drugs (ondansetron and fluconazole) during pregnancy. Ondansetron is a drug used to treat nausea resulting from chemotherapy and radiotherapy. Despite warnings against its use during pregnancy, it is still being prescribed to treat nausea and vomiting among pregnant women. No studies thus far have been of sufficient size to properly consider rarer pregnancy outcomes such as stillbirth and major birth defects. Fluconazole is used to treat fungal infections including candidiasis. While low doses have not been reported to increase congenital abnormalities, high doses have been associated with abnormalities and questions remain regarding its safety during pregnancy.

This study will examine a) the utilisation of ondansetron and fluconazole among pregnant women compared to other anti-nausea drugs and other drugs used to treat fungus infections, respectively; and b) the association between the usage of these two drugs and increased risks of foetal abnormalities. This study will involve data from the Clinical Practice Research Datalink (CPRD) and administrative data from 5 Canadian provinces. The primary outcome will be the occurrence of an adverse pregnancy outcome, defined as at least one of the following events: stillbirth, induced abortion, congenital malformation, and spontaneous abortion.

Technical Summary

Ondansetron is a selective antagonist of the serotonin receptor subtype 5-HT3, having antiemetic properties to treat nausea. Though it is not indicated for nausea and vomiting in pregnancy, it is often prescribed to pregnant women. However, there are potentially severe effects on the foetus. Fluconazole is a highly selective inhibitor of fungal cytochrome P-450 sterol C-14 alpha-demethylation used to treat candidiasis. High doses of fluconazole (400 - 800 mg/day) have been associated with increased risk for congenital malformations. However, questions remain regarding its safety in relation to exposure and dose. To further examine the effect of these two drugs on pregnant women and foetuses, we will conduct a retrospective, population-based cohort study. Pregnancies will be divided into several cohorts (live births, stillbirths, induced abortions, and spontaneous abortions) and use of ondansetron and fluconazole in each group will be assessed. The congenital abnormalities of ondansetron will be compared to diclectin, dimenhydrinate, chlorpromazine, metoclopramide, prochlorperazine, or promethazine. The effects of fluconazole will be compared to polyene antifungals, imidazoles, or triazoles. Where possible, matched sibling cohorts will be used to account for confounding from genetic or socioeconomic factors.

Health Outcomes to be Measured

Stillbirth - Spontaneous abortion - Induced abortion (including termination of pregnancy due to foetal anomaly) - Congenital malformation

Collaborators

Samy Suissa - Chief Investigator - McGill University
Kristian Filion - Corresponding Applicant - McGill University
Anat Fisher - Collaborator - University of British Columbia
Carolina Moriello - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Colin Dormuth - Collaborator - McGill University
J. Michael Paterson - Collaborator - Institute for Clinical Evaluative Sciences ( ICES )
pauline reynier - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Robert Platt - Collaborator - McGill University

Linkages

CPRD Mother-Baby Link;HES Admitted Patient Care;HES Admitted Patient Care;ONS Death Registration Data;ONS Death Registration Data;Practice Level Index of Multiple Deprivation;Practice Level Index of Multiple Deprivation;Pregnancy Register