Ondansetron in Pregnancy and Risk of Adverse Fetal Outcomes

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Pasternak B, et al. "Ondansetron in pregnancy and risk of adverse fetal outcomes". The New England Journal of Medicine. 2013. 368(9):814-823.
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Clinical Question

Is ondansetron use during pregnancy associated with increased risk of adverse fetal outcomes including spontanteous abortion, stillbirth, any major birth defect, preterm delivery, low birth weight, and small size for gestational age?

Bottom Line

Ondansetron use in pregnancy was not associated with a significantly increased risk of major adverse fetal outcomes.

Major Points

Pregnant women exposed to ondansetron were not at increased risk for spontaneous abortion as compared with unexposed women. At Weeks 7 to 12, there was an adjusted HR of 0.49 (95% CI: 0.27-0.91); while at Weeks 13 to 22, an adjusted HR of 0.60 (95% CI: 0.29-1.21). Pregnant women exposed to ondansetron were not at increased risk for stillbirth with an adjusted HR of 0.42 (95% CI: 0.10-1.73). Pregnant women exposed to ondansetron in the first trimester did not have greater prevalence of major birth defects compared to women not exposed with an adjusted prevalence OR of 1.12 (95% CI: 0.69-1.82). Pregnant women exposed to ondansetron before Week 37 of gestation did not have greater prevalence of preterm deliveries compared to women not exposed with an adjusted prevalence OR of 0.90 (95% CI: 0.66-1.25). Exposure to ondansetron any time during pregnancy was not associated with low birth infants or small gestational age at birth.

Guidelines

As of June 2014, no guidelines have been published that reflect the results of this trial.

Design

  • Single nation retrospective cohort study
  • N=608,385
  • Setting: Denmark
  • Years analyzed: 2004-2011
  • Analysis: Propensity score matched
  • Primary outcomes:
    • Spontaneous abortion
    • Stillbirth
    • Major birth defect
    • Low birth weight

Population

Inclusion Criteria

This was an historical cohort study using the National Patient Register of Denmark and the Medical Birth Registry of Denmark for data collection. All pregnancies that resulted in a singleton live birth or stillbirth or ended with any abortive outcome in the period from January 1, 2004 through March 31, 2011 were included in the study.

Exclusion Criteria

  • Pregnancies with missing or implausible gestational age
  • Pregnancies with multiple records on overlapping dates
  • Pregnancies which ended in abortions at a gestational age of less than six weeks due to possible misclassification (early pregnancy losses not always clinically recognized)
  • Women exposed to ondansetron within first six weeks of gestation
  • Pregnancies with missing birth weight information
  • Women who filled ondansetron prescriptions within one month before pregnancy onset

Baseline Characteristics

  • Age: 30 years old
  • Parity of 1: 41-47%
  • Parity of 2: 14-15%
  • Parity of >/=3: 5-6%
  • BMI before pregnancy of 18.5-24.9: 62/65%
  • BMI before pregnancy of 25.0-29.9: 20-22%
  • Diabetes: ~2%
  • Cancer diagnosis in past 6 months: 0.1%
  • 1-2 prescription drugs in past 6 months: ~40%
  • 3-4 prescription drugs in past 6 months: ~21%
  • >/=5 prescription drugs in past 6 months: ~15%

Interventions

Exposure to ondansetron with timing defined by date prescription filled

  • Through 12 gestational weeks for any major birth defect
  • Any time before 37 completed weeks for preterm delivery
  • Any time during pregnancy for analyses involving birth weight
  • Week 7-Week 22 for spontaneous abortion
  • Week 7 until birth for stillbirth

Outcome:

  • Cases of major birth defects (1 year follow-up after birth)
  • Excluded infants with chromosomal aberrations (e.g., Down’s syndrome)
  • Excluded infants with known causes of birth defects (e.g., fetal alcohol syndrome)
  • Spontaneous abortion (fetal loss through 22 gestational weeks)
  • Cases of preterm delivery (prior to 37 completed weeks)
  • Cases of infants born small for gestational age (lowest 10th percentile of the gestational age)
  • Cases of infants born at low birth weight (<2500 g)
  • Cases of stillbirth (fetal loss after 22 completed weeks)

Outcomes

Exposure to ondansetron occurred in 0.3% of pregnancies. The first prescription was filled at a median of 70 gestational day (10 weeks) with interquartile range of 57-88 days. The median number of doses was 10 per prescription and the median number of doses was 30 per pregnancy with interquartile range of 10-65 doses.

Prior to propensity-score matching, the risk of spontaneous abortion was significantly decreased among women exposed to ondansetron compared with unexposed women.

  • Gestational Week 7 to 12: HR of 0.29 (95% CI: 0.17-0.48)
  • Gestational Week 13 to 22: HR of 0.58 (95% CI: 0.36-0.93)

The risk of preterm delivery was significantly increased among women exposed to ondansetron compared with unexposed women prior to propensity-score matching with prevalence OR of 1.28 (95% CI: 1.05-1.55).

After propensity-score matching, >50% of women exposed to ondansetron were hospitalized for hyperemesis of nausea and vomiting during pregnancy. In addition, about 41-43% of women exposed to ondansetron received another antiemetic (metoclopramide, antihistamines, scopolamine, and domperidone).

Pregnant women exposed to ondansetron were not at increased risk for spontaneous abortion as compared with unexposed women.

  • Weeks 7 to 12: adjusted HR of 0.49 (95% CI: 0.27-0.91)
  • Weeks 13 to 22: adjusted HR of 0.60 (95% CI: 0.29-1.21)

Pregnant women exposed to ondansetron were not at increased risk for still birth with adjusted HR of 0.42 (95% CI: 0.10-1.73). Pregnant women exposed to ondansetron in the first trimester did not have greater prevalence of major birth defects compared to women not exposed with adjusted OR of 1.12 (95% CI: 0.69-1.82). Pregnant women exposed to ondansetron before Week 37 of gestation did not have a greater prevalence of preterm deliveries compared to women not exposed with adjusted prevalence OR of 0.90 (95% CI: 0.66-1.25). Exposure to ondansetron at any time during pregnancy was not associated with low birth infants or small gestational age at birth.

Criticisms

  • Study was not powered to assess individual defects
  • The retrospective cohort study design does not allow any control of exposure
  • Data was not available on nausea and vomiting that did not require hospitalization to adjust analysis

Funding

This study was supported by a grant from the Danish Medical Research Council.

Further Reading

Thorpe PG, Gilboa SM, Hernandez-Diaz S, et al. Medications in the first trimester of pregnancy: most common exposures and critical gaps in understanding fetal risk. Pharmacoepidemiol Drug Saf.2013 Sep:22(9):1013-1018.