Nausea and vomiting is a common ailment in pregnancy affecting approximately 70 to 80% of all pregnant women. (1) Ondansetron, a 5-HT3 receptor antagonist, is commonly used to treat nausea and vomiting of varying etiologies including hyperemesis gravidarum. (2) Recently the safety of ondansetron in pregnancy has been called into question. Concern for fetal abnormalities, including cardiac malformations and cleft palates caused by ondansetron have been raised, leading to a petition to the Food and Drug Administration (FDA) to reclassify the agent to category C, D, or X from its current pregnancy category of B. (3) Below we review the pertinent data surrounding the safety of ondansetron in pregnancy.
A retrospective study by Pasternak et al. was published in the New England Journal of Medicine using the Danish National Birth Registry linked with the National Prescription Registry to obtain data between 2004 and 2011.(4) This study is the most well designed and provides the strongest evidence.
- 6,165 patients in their first trimester were included of which 1,233 were exposed to ondansetron. First trimester exposure represent the highest risk for cardiac malformations as the heart is formed during this time.
- Both groups had a 2.9% occurrence of any major birth defect (adjusted prevalence OR = 1.12, CI 0.69-1.82).
- This study accounted for a wide range of maternal co-morbidities to reduce confounding factors.
- Cleft palates were not observed in children born to women exposed to ondansetron.
- Andersen et al. conducted a similar study to Pasternak et al., using the same registries.(5)
- They added 7 years of data to the Pasternak et al. study but only added 15 women who were exposed to ondansetron.
- This study is often cited for finding a higher incidence of cardiac malformations in infants whose mothers were exposed to ondansetron during the first trimester (OR = 2.0, CI 1.3-3.1)
- This study was only published as an abstract, never in a peer-reviewed journal.
- The abstract lacks critical information needed to determine its validity.
- This study cannot be used to make a decision in any data driven way.
- Danielsson et al. conducted a retrospective study using the Swedish Medical Birth Register, Birth Defect Register based on diagnosis at hospital discharge. (6)
- 43,658 infants with malformations were included, of which 1,349 were exposed to ondansetron during the first trimester. 435 exposures were reported by the mother while 914 were identified by the prescription register.
- No statistically significant difference in major malformations was found (OR 0.95, 95% CI 0.72-1.26).
- However, after accounting for some confounding factors the investigators found an increased risk of cardiovascular defects (OR 1.62, 95% CI 1.04-2.14), primarily septal in nature.
- In comparison to the Pasternak et al. study this investigation adjusted for fewer confounders, performed fewer sensitivity analysis and used simpler methods.
- Colvin et al. conducted a retrospective registry review comparing women who gave birth in Western Australia whom received ondansetron via the Australian Pharmaceutical Benefits Scheme from 2002 to 2005 relative to all other births during that time frame (7)
- Of 98,968 pregnancies resulting in birth, 251 women received prescriptions for ondansetron, totalling 263 fetal exposures
- No significant difference was found in any major birth defect in children born to mothers with first trimester exposure (OR 1.2, 95% CI 0.6-2.2).
- A signficantly increased risk of obstructive defects of the renal pelvis and ureter was found (OR 6.2, 95% CI 2.0-19.5); however, the number of cases was less than five, limiting the interpretability of this finding.
- A systematic review was completed by Carstairs that included eight studies meeting criteria for review (8)
- This review found that the majority of the published safety data on ondansetron exposure in early pregnancy suggests the risk for birth defects is small.
- It was noted that two small studies suggested a small increased risk in cardiac defects (as discussed above by Andersen et al. and Danielsson et al.) whereas another large methodologically sound study failed to demonstrate an increased risk of an adverse outcome (as discussed above by Pasternak et al.)
- The investigators concluded that the known risks associated with suboptimally treated nausea and vomiting in pregnancy or hyperemesis gravidarum need to be weighed against the very small potential risks associated with use of ondansetron.
- The association of ondansetron exposure during the first trimester and cleft palate originates from Anderka et al., where a 20% prevalence was observed in infants with mother exposed to ondansetron in the first trimester (n = 55) vs 11% in those who were not exposed (n = 4,479). (9)
- This number is relatively high, especially taking into consideration other much larger studies including Pasternak et al. and Danielsson et al. with 1,233 and 1,349 maternal exposures to ondansetron during the first trimester of pregnancy respectively, with no demonstrated increased risk of cleft palates.
- Exposure to ondansetron was based on maternal recall, introducing a risk for recall bias. Mothers of infants with birth defects are more likely to report exposures than mothers of infants without birth defects.
- The suboptimal methods, strikingly high prevalence and relatively small number of ondansetron exposures (n = 55) make it difficult to associate ondansetron exposure during the first trimester to cleft palates.
FDA Petition to Give Ondansetron a Worse Pregnancy Category
- In October of 2015 the FDA denied a petition to do the following. (3)
- Reclassify the drug ondansetron (Zofran) from pregnancy risk category B to category C, D, or X after evaluation of "new safety information".
- Notify obstetricians and gynecologists (OB /GYNs) that there is insufficient scientifically acceptable evidence that ondansetron is associated with improved treatment outcomes and may lead to adverse maternal and fetal events or outcomes.
- Notify OB/GYNs that promotion of continuous subcutaneous ondansetron pump for the treatment of nausea and vomiting of pregnancy (NVP) is a violation of FDA regulations.
Severe, Uncontrollable Nausea/Vomiting May Have Negative Effects on the Fetus
- Dehydration, electrolyte abnormalities, ketosis, nutritional deficiencies and weight loss can also cause fetal malformations. (10)
- Fejzo et al. reported that mothers who took ondansetron reported less miscarriages and higher rates of live births. (11)
The largest and most well designed study showed no difference in any major birth defect and no cleft palates in those exposed to ondansetron in the first trimester. (4) Studies suggesting ondansetron may cause cardiac malformations were not well designed, failing to adjust for maternal co-morbidities that could themselves cause cardiac malformations, or were not published in peer reviewed journals, only as abstracts. (5-6) The one study suggesting ondansetron exposure may increase the risk of cleft palates was poorly designed and contained a very small number of patients. (7) The FDA has refused to change the current pregnancy category for ondansetron from a “B” given this evidence. (3) Based on the current data, ondansetron appears to be a safe agent for the treatment of nausea and vomiting the pregnancy.
When asked about the safety of ondansetron in pregnancy by patients, providers or other emergency department personnel, one can advise that the best available data shows no increase in congenital defects. The benefit of ondansetron use likely outweighs its risk, especially taking into account the adverse fetal effects that maternal electrolyte abnormalities, dehydration, and nutritional deficiency caused by nausea/vomiting may cause. If ondansetron therapy is refused other possible treatment options include pyridoxine, H1-receptor antagonists such as doxylamine, diphenhydramine, and meclizine, or dopamine receptor antagonists such as metoclopramide, promethazine, and prochlorperazine.
Tony Mixon, PharmD, BCPS
Emergency Medicine/Infectious Disease Clinical Pharmacist
University of Colorado Health- North RegionPeer reviewed by Craig Cocchio, PharmD, BCPS (@iEMPharmD) and Nadia Awad, PharmD, BCPS (@Nadia_EMPharmD)
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- Andersen JR, Jimenez-Solem E, Andersen NL, Poulsen HE. Ondansetron use in early pregnancy and the risk of congenital malformations—a registry based nationwide cohort study. Pharmacoepidemiol Drug Saf 2013;22:13–4.
- Danielsson B, Wikner BN, Källén B. Use of ondansetron during pregnancy and congenital malformations in the infant. Reprod Toxicol 2014;50:134–7.
- Colvin L, Gill AW, Slack-Smith, et al. Off-label use of ondansetron in pregnancy in Western Australia. Biomed Res Int 2013; 2013:909860.
- Carstairs SD. Ondansetron use in pregnancy and birth defects: A systematic review. Obstet Gynecol 2016; 127 (5):878-883.
- Anderka M, Mitchell AA, Louik C, Werler MM, Hernández-Diaz S, Rasmussen SA; National Birth Defects Prevention Study. Medications used to treat nausea and vomiting of pregnancy and the risk of selected birth defects. Birth Defects Res A Clin Mol Teratol 2012;94:22–30
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- Fejzo MS, MacGibbon KW, Mullin PM. Ondansetron in pregnancy and risk of adverse fetal outcomes in the United States. Reprod Toxicol. 2016 Jul;62:87-91.