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Original Investigation
December 18, 2018

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

Author Affiliations
  • 1Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
  • 2Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
  • 3Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
  • 4Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
JAMA. 2018;320(23):2429-2437. doi:10.1001/jama.2018.18307
Key Points

Question  Is the use of ondansetron during pregnancy associated with increased risk of cardiac malformations and oral clefts in offspring?

Findings  In this cohort study including 1.8 million pregnancies, first trimester ondansetron use was associated with an increased risk of oral clefts (3 additional cases per 10 000 women treated; adjusted relative risk, 1.24) but not cardiac malformations.

Meaning  Maternal use of ondansetron in the first trimester was associated with a small increased risk of oral clefts but no increased risk of cardiac malformations.


Importance  Evidence for the fetal safety of ondansetron, a 5-HT3 receptor antagonist that is commonly prescribed for nausea and vomiting during pregnancy, is limited and conflicting.

Objective  To evaluate the association between ondansetron exposure during pregnancy and risk of congenital malformations.

Design, Setting, and Participants  A retrospective cohort study nested in the 2000-2013 nationwide Medicaid Analytic eXtract. The cohort consisted of 1 816 414 pregnancies contributed by 1 502 895 women enrolled in Medicaid from 3 months before the last menstrual period through 1 month or longer after delivery; infants were enrolled in Medicaid for at least 3 months after birth. The final date of follow-up was December 31, 2013. Analyses were conducted between November 1, 2017, and June 30, 2018. Propensity score stratification was used to control for treatment indication and other confounders.

Exposures  Ondansetron dispensing during the first trimester, the period of organogenesis.

Main Outcomes and Measures  Primary outcomes were cardiac malformations and oral clefts diagnosed during the first 90 days after delivery. Secondary outcomes included congenital malformations overall and subgroups of cardiac malformations and oral clefts.

Results  Among 1 816 414 pregnancies (mean age of mothers, 24.3 [5.8] years), 88 467 (4.9%) were exposed to ondansetron during the first trimester. Overall, 14 577 of 1 727 947 unexposed and 835 of 88 467 exposed infants were diagnosed with a cardiac malformation, for an absolute risk of 84.4 (95% CI, 83.0 to 85.7) and 94.4 (95% CI, 88.0 to 100.8) per 10 000 births respectively. The absolute risk of oral clefts was 11.1 per 10 000 births (95% CI, 10.6 to 11.6; 1921 unexposed infants) and was 14.0 per 10 000 births (95% CI, 11.6 to 16.5; 124 exposed infants). The risk of any congenital malformation was 313.5 per 10 000 births (95% CI, 310.9 to 316.1; 54 174 unexposed infants) and was 370.4 (95% CI, 358.0 to 382.9; 3277 exposed infants). The adjusted relative risk (RR) for cardiac malformations was 0.99 (95% CI, 0.93 to 1.06) and the adjusted risk difference (RD) was −0.8 (95% CI, −7.3 to 5.7 per 10 000 births). For oral clefts, the adjusted RR was 1.24 (95% CI, 1.03 to 1.48) and the RD was 2.7 (95% CI, 0.2 to 5.2 per 10 000 births). The adjusted estimate for congenital malformations overall was an RR of 1.01 (95% CI, 0.98 to 1.05) and an RD of 5.4 (95% CI, −7.3 to 18.2 per 10 000 births).

Conclusions and Relevance  Among offspring of mothers enrolled in Medicaid, first-trimester exposure to ondansetron was not associated with cardiac malformations or congenital malformations overall after accounting for measured confounders but was associated with a small increased risk of oral clefts.