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