Nausea and vomiting can often occur in the first trimester of pregnancy, with up to 15 per cent of women requiring antiemetic medication and one per cent requiring inpatient management and multiple medications. As this coincides with the period of fetal organogenesis, it is important that medications used in the first trimester are not teratogenic.

Ondansetron, a 5-HT₃ receptor antagonist, is indicated for post-operative, chemotherapy-induced and radiation-induced nausea and vomiting. It has also been shown to be at least as effective as other antiemetics in treating nausea and vomiting in pregnancy, and highly efficacious in treating hyperemesis gravidarum.¹ Early studies suggested that ondansetron does not increase the risk of fetal abnormality, however, recent data has been more conflicting. This article aims to review the available literature with regards to the safety and/or potential risks of ondansetron in pregnancy.

A small prospective cohort study was first published in 2004 by researchers in Canada and Australia.² Women who called a phone pregnancy counselling service in the first trimester of pregnancy and were taking ondansetron at the time of the call were enrolled. Comparison groups included women taking other antiemetics and women taking no anti-nausea medication at all. The study found no statistically significant differences among the groups in the incidence of major malformations, although the authors acknowledged that the study was underpowered, with only about 170 women in each group.

A Swedish cohort was published in 2005³ using data from the Swedish Medical Birth Register from 1995 to 2002. Women reporting the use of any antiemetics were compared with all women who gave birth during the study period. Only 65 women in this cohort used ondansetron in the first trimester and those fetuses exposed were not found to have an increased incidence of major malformations. However, this study was also underpowered to detect any significant difference in the risk of fetal malformations with the use of ondansetron.
Anderka et al published a case-controlled study in 2012, looking at the use of antiemetics to treat nausea and vomiting in pregnancy and the risk of selected birth defects.⁴ This study used data from the US National Birth Defects Prevention Study (1997–2004). Analysis was limited to four common non-cardiac birth defect categories. Mothers of babies were interviewed about nausea and vomiting in pregnancy and the use of prescription medications, of which up to 75 different medications were used. There was a positive association between the use of ondansetron and cleft palate, with an adjusted odds ratio (OR) of 2.37 (95% CI 1.18–4.76), although the numbers exposed were small.

Pasternak et al published results from a large cohort using data from the Danish Medical Birth Registry (2004–2011), matched with data from the Danish National Prescription Registry, to identify women who had filled prescriptions for ondansetron in the first trimester.⁵ There were 608,385 pregnancies included, of whom 1233 women had been exposed to ondansetron in the first trimester. These women were matched in a 1:4 ratio with unexposed pregnant women. There were no significant differences in major malformations between exposed (2.9 per cent) and unexposed groups (2.9 per cent). There were no cases of cleft palate in the group exposed to ondansetron. The authors concluded that ondansetron was not associated with an increased risk of major congenital anomalies when used for treatment of nausea and vomiting in pregnancy.

Andersen et al looked at data from the same Danish national registries, but across a wider time frame (1997–2010), to assess the teratogenic effects of ondansetron exposure.⁶ Of 897,018 births, 1248 women took ondansetron. This study found 58 (4.7 per cent) major congenital malformations in the exposed group, compared with 31,357 (3.5 per cent) in the unexposed group, with an OR of 1.3 (95% CI 1.0–1.7). An increased prevalence of cardiac defects accounted for most of these malformations, with an OR of 2.0 (95% CI 1.3–3.1).

Although there was a considerable time overlap between the two Danish cohorts, there were only an additional 15 women exposed to ondansetron in the larger cohort, possibly reflecting the infrequent prescribing of ondansetron for nausea and vomiting in pregnancy in the earlier years. However, in spite of the very few additional exposures, the second cohort reported significantly more major congenital malformations; 58 (4.7%) versus 36 (2.9%) in the exposed group, and 31,357 (3.5%) versus 141 (2.9%) in the unexposed group. It is difficult to ascertain the reason behind the reported differences, especially given that the larger cohort study did not publish its methodology in detail.

In 2014, Colvin et al published results from a cohort of 96,968 women who gave birth from 2002 to 2005 in Western Australia.⁷ Of these women, 211 babies were exposed to ondansetron in the first trimester. They found no significantly increased risk of major birth defects with first trimester exposure, 4.9 per cent versus 4.1 per cent (OR 1.2; 95% CI 0.6–2.2). They did report a significantly increased risk of obstructive renal defects, however, the absolute number of these cases was less than five.

In the same year, a Swedish cohort was published, using data from the Swedish Medical Birth Register combined with the Swedish Register of Prescribed Drugs.⁸ This study identified 1349 infants born to women who had taken ondansetron in early pregnancy from 1998 to 2012 (with a total of 1.5 million births). No statistically significant increased risk for major malformations was found, however, there was a statistically significant increased risk for cardiovascular defects (OR 1.62; 95% CI 1.02-2.14). Most of these cardiac defects were septal defects. The study concluded that the teratogenic risk with ondansetron is low, but an increased risk of a cardiac septal defect is likely.

In all of these studies, the overall number of women using ondansetron in the first trimester of pregnancy was comparatively low, limiting the power of these studies to detect significant differences in any individual fetal congenital malformations. Cohort studies are also subject to bias, which may include systematic, recall or reporting biases, depending on the methodology used.

A systematic review was published in 2016⁹ that summarised the above conflicting trials. Taking into account the results from the three largest cohorts that showed no overall increase in birth defects, including the two studies demonstrating a small increase in risk of cardiac defects specifically, the author suggested that ondansetron should be reserved for women with nausea and vomiting of pregnancy, whose symptoms have not been adequately controlled by other methods.

RANZCOG does not currently have a published guideline on management of nausea and vomiting of pregnancy, nor on hyperemesis gravidarum. The Royal College of Obstetricians and Gynaecologists Green-Top Guideline states that while available evidence indicates that ondansetron is safe and effective, due to limited data, it should be used as second-line therapy.¹⁰ The American College of Obstetricians and Gynecologists recommends discussing available data with patients and weighing the risks and benefits of ondansetron use on a case-by-case basis in women at less than 10 weeks’ gestation.¹¹

In summary, nausea and vomiting of pregnancy and hyperemesis gravidarum are common and potentially debilitating conditions for women during pregnancy. While ondansetron is commonly used and is very effective in management of nausea and vomiting outside of pregnancy, the paucity of data on teratogenicity limits its use in pregnancy, especially in the first trimester. More studies are needed in this area to guide clinicians in using ondansetron in women who do not respond to standard antiemetics.

1. Boelig RC, Barton SJ, Saccone G, et al. Interventions for treating hyperemesis gravidarum. Cochrane Database Syst Rev. 2016;(5):CD010607.
2. Einarson A, Maltepe C, Navioz Y, et al. The safety of Ondansetron for nausea and vomiting of pregnancy: a prospective comparative study. BJOG. 2004;111:940-3.
3. Asker C, Norstedt Wikner B, Källén B. Use of antiemetic drugs in pregnancy in Sweden. Eur J Clin Pharmacol. 2005; 61(12):899-906.
4. Anderka M, Mitchell AA, Louik C, et al. Medications used to treat nausea and vomiting of pregnancy and the risk of selected birth defects. Birth Defects Res A Clin Mol Teratol. 2012;94(1):22-30.
5. Pasternak B, Svanström H, Hviid A. Ondansetron in pregnancy and the risk of adverse fetal outcomes. N Engl J Med. 2013;368(9):814-23.
6. Andersen JT, Jiminez-Solem E, Andersen NL, et al. Ondansetron use in early pregnancy and the risk of congenital malformations – a register-based nationwide cohort study. Program and abstracts of the 29th International Conference on Pharmacoepidemiology & Therapeutic Risk Management; August 25-28, 2013; Montreal, Quebec, Canada. Abstract 25, Pregnancy session 1.
7. Colvin L, Gill AW, Slack-Smith L, et al. Off-label use of Ondansetron in pregnancy in Western Australia. Biomed Res Int. 2013; 2013:909860.
8. Danielsson B, Wikner BN, Kallen B. Use of Ondansetron during pregnancy and congenital malformations in the infant. Reprod Toxicol. 2014;50:134-137.
9. Carstairs SD. Ondansetron use in pregnancy and birth defects: a systematic review. Obstet Gynecol. 2016;127(5):878-83.
10. Royal College of Obstetricians and Gynaecologists. The management of nausea and vomiting of pregnancy and hyperemesis gravidarum (Green-top Guideline No. 69), June 2016.
11. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 189: nausea and vomiting of pregnancy. Obstet Gynecol. 2018;131:15-30.