Intravenous Ondansetron in Pregnancy and Risk of Congenital Malformations

Abstract

A population-based cohort study previously evaluated the association between first-trimester exposure to the oral formulations of ondansetron and congenital malformations. After accounting for potential confounding variables, there was no significant association with congenital malformations overall or cardiac malformations, but a small increased risk of oral clefts could not be excluded. 1 Subsequent research has suggested that intravenous administration of ondansetron may be associated with greater risks of cardiac malformations and oral clefts. 2 Potential explanations for the apparent difference in teratogenic effect of intravenous compared with oral formulations include (1) residual confounding by indication and associated factors (eg, nutritional deficiencies) in women with hyperemesis severe enough to require intravenous medication, (2) higher doses administered intravenously vs orally, and (3) higher specificity for exposure because studies of oral use in health care utilization data are based on dispensed medication, and not all women may consume the medication as prescribed. We therefore conducted a follow-up study to examine the association between intravenous ondansetron and congenital malformations. Methods | The data source, study design, and analytic methods were the same as described in our previously published evaluation of oral ondansetron. 1 Briefly, we used a motherinfant-linked cohort nested in the 2000 to 2014 Medicaid Analytic eXtract. 3 The research was approved by the institutional review board of Brigham and Women's Hospital, with waiver of informed consent.

Association of first trimester prescription opioid use with congenital malformations in the offspring: population based cohort study

“…The development of the MAX pregnancy cohort by linking maternal and infant claims records has been previously described 18 ; it has been used extensively to study the safety of drugs in pregnancy. 19 20 21 22 23 24 25 26 The MarketScan pregnancy cohort was developed similarly, by linking maternal and infant claims. Both data sources include information on maternal demographics, diagnoses, and procedures received during inpatient, outpatient, or emergency department visits, and dispensed outpatient prescription drugs.…”

“…The study used pregnancy cohorts nested in the Medicaid Analytic eXtract (MAX), which includes data on healthcare use for Medicaid beneficiaries nationwide, for the years 2000 to 2014, and the IBM Health MarketScan Research Database (MarketScan), which includes data on healthcare use from a nationwide sample of commercially insured beneficiaries, for the years 2003 to 2015. The development of the MAX pregnancy cohort by linking maternal and infant claims records has been previously described18; it has been used extensively to study the safety of drugs in pregnancy 1920212223242526. The MarketScan pregnancy cohort was developed similarly, by linking maternal and infant claims.…”

Ondansetron in pregnancy revisited: Assessment and pregnancy labelling by the European Medicines Agency (EMA) & Pharmacovigilance Risk Assessment Committee (PRAC).

“…The resulting propensity-score adjusted inferential analysis of about 24.000 pregnancies exposed to intravenous ondansetron did not result in increased risk of cardiac malformations (RR 0.97; 95% CI 0.86-1.10), oral clefts (RR 0.95; 95% CI 0.63-1.43), or any congenital malformation(RR 1.02; 95% CI 0.96-1.08). Unadjusted analyses suggested a small increased risk for cardiac and any malformation (11). These data strongly mitigate the previous data on intravenous ondansetron (9).…”

“…In January 2020, Huybrechts et al published an additional study on intravenous administration of ondansetron in early pregnancy and risk of congenital malformations (11). In this study, the authors revisited the study population from their original paper, but restricted their analysis to those women who received intravenous ondansetron in first trimester (8).…”

Validating the effect of Ondansetron and Mirtazapine In Treating hyperemesis gravidarum (VOMIT): protocol for a randomised placebo-controlled trial

“…However, two recent cohort studies, one including almost 90 000 pregnancies exposed to prescription ondansetron and one including over 23 000 pregnancies exposed to intravenous ondansetron, did not find an association between exposure and cardiac or general congenital malformations in the newborn. They did, however, find that exposure was associated with a small increased risk of oral cleft (3 in 10 000) 33 34. Considering this relatively small increased risk and the fact that ondansetron is already being used in pregnant women with hyperemesis gravidarum, compared with the risk of severe hyperemesis gravidarum, we find it ethically acceptable to randomise participants to treatment with ondansetron.…”