Ondansetron: small increased risk of oral clefts following use in the first 12 weeks of pregnancy

Recent epidemiological studies suggest exposure to ondansetron during the first trimester of pregnancy is associated with a small increased risk of the baby having a cleft lip and/or cleft palate.

Ondansetron: evidence and advice

Ondansetron (Zofran), a 5-HT3 receptor antagonist, is authorised for the management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy (in adults and children older than 6 months) and for the prevention and treatment of nausea and vomiting after surgery (in adults and children older than 1 month).

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. There is a growing body of evidence on the use of ondansetron in pregnancy that does not suggest an increase in the risk of overall congenital malformations combined (for example publications[footnote 1] [footnote 2] [footnote 3]).

Recent epidemiological studies report a small increased risk of orofacial malformations in babies born to women who used ondansetron in early pregnancy.[footnote 1] [footnote 4] Key evidence was an observational study of 1.8 million pregnancies in the USA of which 88,467 (4.9%) were exposed to oral ondansetron during the first trimester of pregnancy. The study reported that ondansetron use was associated with an additional 3 oral clefts per 10,000 births (14 cases per 10,000 births versus 11 cases per 10,000 births in the unexposed population).[footnote 1] These data were recently reviewed within Europe and considered to be robust. As for all licensed medicines, the safety of ondansetron will be continuously monitored by the MHRA and relevant emerging information will be considered as it becomes available.

Outside of its authorised indications, ondansetron is also used second line for treating women with hyperemesis gravidarum, a severe and potentially life-threatening condition.[footnote 5] If a physician considers, based on their professional judgement, the available evidence and the risks for mother and baby of malnutrition in early pregnancy, that a licensed treatment (for example doxylamine/pyridoxine, Xonvea[footnote 6]) is not suitable or not sufficient alone to control severe nausea and vomiting in pregnancy, and there is a special clinical need to use ondansetron, then this decision should be made in consultation with the patient after she has been fully informed of the potential benefits and risks of the different treatment options.

Prescribers should refer to clinical guidance if treatment with ondansetron is considered for severe nausea and vomiting in pregnancy.[footnote 5]

Detailed findings of studies

A retrospective cohort study[footnote 1] of a medical claims database in the USA included 1,816,414 pregnancies between 2000 and 2013, of which 88,467 (4.9%) were associated with a prescription of ondansetron during the first trimester. Exposure to ondansetron during the first 12 weeks of pregnancy was linked with a small but statistically significant increased risk of orofacial cleft defects (adjusted relative risk [aRR] 1.24, 95% CI 1.03–1.48).

A case–control study of another US medical claims database[footnote 4] included 864,083 mother-infant pairs seen between 2000 and 2014, and found a non-statistically significant trend towards an increased risk of orofacial cleft defects in babies exposed to ondansetron compared with those not exposed to any antiemetic (adjusted odds ratio [OR] 1.30, 95% CI 0.75–2.25). This study also linked ondansetron use during the first trimester with an increased risk of cardiac defects (adjusted OR 1.43, 95% CI 1.28–1.61).[footnote 4] However, this finding conflicts with results from other studies. For example, Huybrechts and colleagues[footnote 1] did not find a significant association for cardiac defects after adjusting for pre-defined confounding factors (aRR 0.99, 95% CI 0.93–1.06).

The recent observational studies have some limitations inherent to the data sources, but the findings are considered sufficiently robust to indicate that use of ondansetron during the first trimester of pregnancy is associated with a small increased risk of the baby having a cleft lip and/or cleft palate.

If the clinical decision is to offer ondansetron in pregnancy, women must be counselled on the potential benefits and risks of use, both to her and to her unborn baby and the final decision should be made jointly.

Report adverse drug reactions in pregnancy

Report any suspected adverse drug reactions in the mother or child, including adverse pregnancy outcomes, following use of a medicine in pregnancy on a Yellow Card.

All healthcare professionals, patients, parents, and caregivers can report any suspected adverse reactions associated with medicines to the Yellow Card Scheme.

It is easy to report on the Yellow Card website or via the Yellow Card app. Download the App via iTunes Yellow Card for iOS devices or via PlayStore Yellow Card for Android devices.

Article citation: Drug Safety Update volume 13, issue 6: January 2020: 2.

  1. Huybrechts KF, et al. Association of maternal first-trimester ondansetron use with cardiac malformations and oral clefts in offspring. JAMA 2018; 320: 2429–37.  2 3 4 5

  2. Lavecchia M, et al. Ondansetron in Pregnancy and the Risk of Congenital Malformations: a Systematic Review. J Obstet Gynaecol Can 2018; 40: 910–18. 

  3. Kaplan YC, et al. Use of ondansetron during pregnancy and the risk of major congenital malformations: a systematic review and meta-analysis. Reprod Toxicol 2019; 86: 1–13. 

  4. Zambelli-Weiner A, et al. First trimester ondansetron exposure and risk of structural birth defects. Reprod Toxicol 2019; 83: 14–20.  2 3

  5. Royal College of Obstetrics and Gynaecology. The Management of Nausea and Vomiting of Pregnancy and Hyperemesis Gravidarum. Green-top Guideline No. 69. June 2016.  2

  6. Xonvea [doxylamine succinate, pyridoxine hydrochloride] is authorised for treatment of nausea and vomiting in pregnancy for patients who do not respond to conservative management. 

Published 27 January 2020