Safety of Intravenous Ondansetron in Pregnancy

BACKGROUND AND PURPOSE:

  • Oral formulations of ondansetron (Zofran) appear safe for use in first trimester
  • However, IV use has been associated with greater risks of cardiac malformations and oral clefts
  • In a research letter, Huybrechts et al. (JAMA, 2019) sought to determine the association between IV ondansetron and congenital malformations

METHODS:

  • Retrospective cohort study
    • Follow-up on previous 2018 paper in JAMA (see ‘Related ObG Topics’ below)
    • In original study, women were considered exposed if they filled at least 1 ondansetron prescription during the first trimester  
  • Exposures in the current study
    • Ondansetron injection during the first trimester
    • Control group with no exposure to ondansetron from 3 months before pregnancy through the end of the first trimester
  • Primary outcomes
    • Cardiac malformations
    • Oral clefts
    • Congenital malformations overall

RESULTS:

  • Overall, 1,800,594 pregnancies were included
    • 1.3% received at least one ondansetron injection during the first trimester
    • Characteristics of exposed and unexposed women were well balanced after propensity score stratification
  • Cardiac malformations (not significantly different)
    • Adjusted relative risk (RR) 0.97 (95% CI, 0.86 to 1.10) per 10,000 births
    • Adjusted risk difference (RD) −2.9 (95% CI, −15.7 to 9.8) per 10,000 births
  • Oral clefts (not significantly different)
    • Adjusted RR 0.95 (95% CI, 0.63 to 1.43) per 10,000 births
    • Adjusted RD −0.5 (95% CI, −4.5 to 3.5) per 10,000 births
  • Overall malformations (not significantly different)
    • RR 1.02 (95% CI, 0.96 to 1.08) per 10,000 births
    • RD 7.1 (95% CI, −17.9 to 32.2) per 10,000 births

CONCLUSION:

  • IV ondansetron was not associated with an increased risk of cardiac malformations, oral clefts, or congenital malformations overall
  • The authors conclude that evidence “suggests that ondansetron is not a major teratogen”

Learn More – Primary Sources:

Intravenous Ondansetron in Pregnancy and Risk of Congenital Malformations

Safety of First Trimester Ondansetron Exposure During Pregnancy

BACKGROUND AND PURPOSE:

  • Ondansteron, a 5-HT3 receptor agonist, is used to treat nausea and vomiting in pregnancy
  • Safety data on the association between ondansetron and birth defects are limited
  • Huybrechts et al. (JAMA., 2018) sought to evaluate whether ondansetron exposure during pregnancy is associated with risk of congenital malformations, with a focus on cardiac and oral clefting defects

METHODS:

  • Retrospective cohort study
    • Data derived from the nationwide Medicaid Analytic eXtract (MAX)
    • Pregnant women registered 3 months before the last menstrual period through 1 month or longer after delivery
  • Data analyzed comparing
    • Ondansetron (exposure) during the first trimester vs control group
  • Primary outcomes (diagnosed during the first 90 days after delivery)
    • Cardiac malformations
    • Oral clefts
  • Secondary outcomes included
    • Congenital malformations overall
    • Subgroups of cardiac malformations and oral clefts

RESULTS:

  • 1,816,414 pregnancies were included
    • Mean maternal age: 24.3 years
    • 88,467 (4.9%) were exposed to ondansetron during the first trimester
  • Cardiac Malformations (absolute risk)
    • Unexposed: 84.4 per 10,000 births ( 95% CI, 83.0 to 85.7)
    • Exposed: 94.4 per 10,000 births (95% CI, 88.0 to 100.8)
  • Oral clefts (absolute risk)
    • Unexposed: 11.1 per 10,000 births (95% CI, 10.6 to 11.6)
    • Exposed: 14.0 per 10,000 births (95% CI, 11.6 to 16.5)
  • Any congenital malformation (absolute risk)
    • Unexposed: 313.5 per 10,000 births (95% CI, 310.9 to 316.1)
    • Exposed: 370.4 per 10,000 births (95% CI, 358.0 to 382.9)
  • Cardiac malformations (relative risk)
    • Adjusted relative risk (RR): 0.99 (95% CI, 0.93 to 1.06)
  • Oral clefts (relative risk)
    • Adjusted RR: 1.24 (95% CI, 1.03 to 1.48)
  • Congenital malformations (relative risk)
    • Adjusted RR: 1.01 (95% CI, 0.98 to 1.05)

CONCLUSION:

  • First-trimester exposure to ondansetron was not associated with cardiac malformations or overall congenital malformations
  • There may be a “small increased risk of oral clefts”

Learn More – Primary Sources:

Association of Maternal First-Trimester Ondansetron Use With Cardiac Malformations and Oral Clefts in Offspring

Ondansetron for Nausea During Pregnancy – Is There a Risk for Birth Defects?

BACKGROUND AND PURPOSE:

  • Ondansetron, a serotonin receptor antagonist, may be used as a last resort in women with nausea and vomiting in pregnancy
    • Data currently is limited regarding birth defect risk
  • Lavecchia et al. (Journal of Obstetrics and Gynaecology Canada, 2018) examined the association between prenatal exposure to ondansetron, to treat nausea during pregnancy, and congenital malformations

METHODS:

  • Systematic database search and extraction
    • RCTs, cohort, and case-control studies that reported fetal outcomes of prenatal ondansetron exposure

RESULTS:

  • 10 epidemiological studies out of 690 were included:
    • 5 large retrospective cohort studies | 2 prospective observational studies | 2 population-based case-controls | 1 retrospective case series
    • Only 3 large population-based cohort studies that were designed to specifically evaluate the risk of ondansetron exposure and congenital malformations
    • Most studies evaluated exposure during the first trimester
  • One case-control study identified an association between prenatal exposure to ondansetron and cleft palate and another cohort study found an increased risk of cardiovascular defects
    • Neither of these findings were reproduced in the other studies, in particular the large population-based cohort study (including 1849 ondansetron pregnancies)
    • Study showing cardiovascular defects indicates that the majority of ondansetron exposure was after 56 days (following cardiac organogenesis)
    • Study showing clefting could be due to confounding due to exposure to multiple medications

CONCLUSION:

  • The authors state that their “literature and rigorous independent review of all data on ondansetron use in pregnancy and the risk of congenital malformations did not yield significant safety concerns.”
  • Further investigation, using large prospective cohort studies, is needed to confirm these findings

Learn More – Primary Sources:

Ondansetron in Pregnancy and the Risk of Congenital Malformations: A Systematic Review