Antiemetic
PREGNANCY RECOMMENDATION: Human Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
Consistent with the animal data, most human pregnancy data for ondansetron suggest that the risk of birth defects is low. However, in many studies ondansetron was started after organogenesis. Moreover, a large Danish study reported a 2-fold increased risk of cardiac anomalies. Thus, additional data are required to determine the risk. Consequently, if indicated, starting ondansetron therapy after 10 weeks of gestation should be considered.
FETAL RISK SUMMARY
Ondansetron is a selective 5-HT3 receptor antagonist. It is an antiemetic that is indicated for the prevention and treatment of nausea and vomiting induced by chemotherapy, radiotherapy, and postoperative. The drug is extensively metabolized to metabolites that are unlikely to contribute to the parent drug’s biological activity. The mean elimination half-life of a single 8-mg dose in women of reproductive age (18–40 years) is 3.5 hours (1).
No adverse effects on fertility or on the fetus were observed in reproduction studies in rats and rabbits with oral doses up to 15 and 30 mg/kg/day, respectively (1).
It is not known if ondansetron crosses the human placenta. The molecular weight (about 293) and the moderate elimination half-life suggest that the drug will cross to the embryo–fetus, but the extensive metabolism may limit the amount of parent drug crossing the placenta.
Ondansetron has been used in the treatment of hyperemesis gravidarum (2–6). A 21-year-old primigravida with severe nausea and vomiting was treated unsuccessfully for approximately 4 weeks, beginning at 6 weeks’ gestation, with IV metoclopramide, 10 mg 3 times daily, rectal dimenhydrinate, 100 mg twice daily, and IV fluids (2). Because her condition was considered life-threatening for both her and her fetus, ondansetron 8 mg IV 3 times daily was instituted at 11 weeks’ gestation and continued for 14 days. Significant improvement was noted in the patient’s condition from the second day of therapy. The woman eventually gave birth at term to a healthy 3.2-kg girl.
A second report on the use of ondansetron for severe NVP involved a 22-year-old woman with renal impairment and nephrotic syndrome (3). Treatment with the antiemetic was begun at 30 weeks’ gestation with 8 mg IV 3 times daily for 1 day, then orally (dose not specified) until 33 weeks’ gestation. A healthy 2052-g female infant was delivered at 36 weeks by elective cesarean section. The infant remained in good health at an unspecified follow-up period.
A randomized, double-blind study, first published as an abstract (4) and then as a full report (5), compared IV ondansetron (10 mg) (N = 15) with IV promethazine (50 mg) (N = 15) for the treatment of hyperemesis gravidarum. Both drugs were given as an initial dose followed by as-needed doses every 8 hours. The mean gestational ages of the two groups at the start of therapy were 11.0 and 10.2 weeks, respectively. No differences were observed between the two groups in terms of duration of hospitalization, nausea score, number of doses received, treatment failures, and daily weight gain. The only adverse effect observed was sedation in 8 women who received promethazine compared with none in the ondansetron group. No mention was made of the pregnancy outcomes in either group.
Ondansetron, 8 mg IV twice daily, was administered to a woman at 14 weeks’ gestation after 6 weeks of unsuccessful therapy with intermittent use of promethazine, prochlorperazine, metoclopramide, and IV hydration (6). IV ondansetron was able to control her vomiting, but not her nausea, and 2 days later she was converted to oral therapy (4 mg) that was taken intermittently (1–2 times daily) until 33 weeks’ gestation. Nausea occurred throughout her pregnancy, with occasional episodes of vomiting. She eventually delivered a healthy, 2.7-kg male infant at 39 weeks’ who was doing well at early follow-up.
A prospective comparative observational study, published in 2004, compared three groups of pregnant women (N = 176 in each group) for the treatment of NVP: ondansetron, other antiemetics, and nonteratogen exposures (7). There were no significant differences between the three groups in terms of life births, spontaneous abortions (SABs), elective abortions, stillbirths, birth weight, and gestational age at birth. In the ondansetron group, there were six (3.5%) major anomalies compared with three (1.8%) in each of the other two groups (p = 0.52). There were three cases of hypospadias in the ondansetron group compared with one in the other groups (p = 0.25) (7).
A 2012 study, using data from the National Birth Defects Prevention Study (NBDPS), examined whether NVP or its treatment was associated with the most common noncardiac birth defects in the NBDPS: nonsyndromic cleft lip with or without cleft palate, cleft palate alone, neural tube defects, and hypospadias (8). For NVP, there were modest risk reductions for cleft lip/palate (adjusted odds ratio [aOR] 0.87, 95% confidence interval [CI] 0.77–0.98) and hypospadias (aOR 0.84, 95% CI 0.72–0.98). For NVP treatments in the 1st trimester, there were increased risks for proton pump inhibitors and hypospadias (aOR 4.36, 95% CI 1.21–15.81), corticosteroids and hypospadias (aOR 2.87, 95% CI 1.03–7.97), and ondansetron and cleft palate (aOR 2.37, 95% CI 1.18–4.76), whereas antacids had a reduced risk for cleft lip/palate (aOR 0.58, 95% CI 0.38–0.89). The authors commented that the three associations could be chance findings but warranted further study (8).
In a 2013 study from Denmark, pregnant women exposed to ondansetron were compared in a 1:4 ratio with women not exposed (9). There was no increased risk for SAB that occurred in 1.1% of exposed compared with 3.7% of unexposed women during weeks 7–12 (hazard ratio [HR] 0.49, 95% CI 0.27–0.91) or for weeks 13–22 (1.0% vs. 2.1%, respectively, HR 0.60, 95% CI 0.29–1.21). There also was no increased risk for stillbirth (0.3% vs. 0.40%, respectively, HR 0.42, 95% CI 0.10–1.73), any major birth defect (2.9% vs. 2.9%, prevalence OR [pOR] 1.12, 95% CI 0.69–1.82), preterm birth (6.2% vs. 5.2%, pOR 0.90, 95% CI 0.66–1.25), low-birth-weight infant (4.1% vs. 3.7%, pOR 0.76, 95% CI 0.51–1.13), or small-for-gestational-age infant (10.4% vs. 9.2%, pOR 1.13, 95% CI 0.89–1.44)(9).
Although this study found no association with an increased risk of some adverse fetal outcomes, the question whether ondansetron causes birth defects remains unanswered. This is true because the median gestational age when the first ondansetron prescription was filled was 10 weeks. Thus, half of the exposed women were beyond the period (i.e., organogenesis) when a drug could cause structural anomalies.
A 2014 letter noted that the above study and a second study from Denmark were presented at the 2013 International Society of Pharmacoepidemiology meeting in Montreal (10). The second Danish study (11), using the same national registries but covering more years (1997–2010 vs. 2004–2011) and more pregnant women (897,108 vs. 608,835), reported a 2-fold increased risk of cardiac anomalies (OR 2.0, 95% CI 1.3–3.1). Other issues raised in the letter were concerns for maternal harm caused from QT prolongation, torsade de pointes, and serotonin syndrome (10).
BREASTFEEDING SUMMARY
No reports describing the use of ondansetron during human lactation have been located. The molecular weight (about 293) and the moderate elimination half-life (3.5 hours) suggest that the drug will be excreted into breast milk, but the extensive metabolism may limit the amount in milk. The effect of this exposure on a nursing infant is unknown.
References
1.Product information. Zofran. GlaxoSmithKline, 2012.
2.Guikontes E, Spantideas A, Diakakis J. Ondansetron and hyperemesis gravidarum. Lancet 1992;340:1223.
3.World MJ. Ondansetron and hyperemesis gravidarum. Lancet 1993;341:185.
4.Sullivan CA, Johnson CA, Roach H, Martin RW, Stewart DK, Morrison JC. A prospective, randomized, double-blind comparison of the serotonin antagonist ondansetron to a standardized regimen of promethazine for hyperemesis gravidarum. A preliminary investigation (abstract). Am J Obstet Gynecol 1995;172:299.
5.Sullivan CA, Johnson CA, Roach H, Martin RW, Stewart DK, Morrison JC. A pilot study of intravenous ondansetron for hyperemesis gravidarum. Am J Obstet Gynecol 1996;174:1565–8.
6.Tincello DG, Johnstone MJ. Treatment of hyperemesis gravidarum with the 5-HT3 antagonist ondansetron (Zofran). Postgrad Med J 1996;72:688–9.
7.Einarson A, Maltepe C, Navioz Y, Kennedy D, Tan MP, Koren G. The safety of ondansetron for nausea and vomiting of pregnancy: a prospective comparative study. Br J Obstet Gynaecol 2004;111:940–3.
8.Anderka M, Mitchell AA, Louik C, Werler MM, Hernandez-Diaz S, Rasmussen SA, and the National Birth Defects Prevention Study. Medications use to treat nausea and vomiting of pregnancy and the risk of selected birth defects. Birth Defects Res (Part A) 2012;94:22–30.
9.Pasternak B, Svanstrom H, Hviid A. Ondansetron in pregnancy and risk of adverse fetal outcomes. NEJM 2013;368:814–23.
10.Koren G. Scary science: ondansetron safety in pregnancy – two opposing results from the same Danish registry. Ther Drug Monit 2014;36:1–2.
11.Andersen JT, Jimenez-Solem E, Andersen NL, et al. Ondansetron use in early pregnancy and the risk of congenital malformations—a registry based nationwide control study. International Society of Pharmaco-epidemiology. Montreal, Canada; 2013. Abstract 25, Pregnancy Session 1. As cited by Koren G. Scary science: ondansetron safety in pregnancy—two opposing results from the same Danish registry. Ther Drug Monit 2014;36:1–2.