Darren J. Hein, PharmD

Disclosures

December 03, 2015

Question

Ondansetron is frequently prescribed for morning sickness, but is it safe?

Darren J. Hein, PharmD
Assistant Professor, Department of Pharmacy Practice, Creighton University School of Pharmacy and Health Professions, Omaha, Nebraska

Nausea and vomiting in pregnancy occurs in up to 80% of women, with about 15% requiring antiemetic medication.[1,2] Unfortunately, nausea and vomiting peak during the first trimester of pregnancy, coinciding with greatest fetal susceptibility to teratogenic effects of medications.[3]

Ondansetron (Zofran®) is a 5-HT3 receptor antagonist indicated for the prevention of chemotherapy-induced nausea and vomiting, radiation-induced nausea and vomiting, and postoperative nausea and vomiting. Although it is not approved by the US Food and Drug Administration (FDA) for the treatment of nausea and vomiting in pregnancy, ondansetron is the most common antiemetic medication prescribed to pregnant women.[4,5] Despite its frequent off-label use, data on the effects of ondansetron on the developing fetus are limited and conflicting.

In 2004, researchers[6] from Canada and Australia published the results of a cohort study comparing the rates of miscarriage, stillbirth, and major birth defects among pregnant women receiving ondansetron, other antiemetics, or no antiemetics (n = 176 in each group). All women who received ondansetron were in the first trimester. No significant differences among the groups for all of the adverse pregnancy outcomes were observed; however, this industry-sponsored study was powered to detect only a 3.5-fold or greater increased risk in major birth defects.

A larger, case/control study[2] associated ondansetron with a significantly increased risk for cleft palate. The odds of cleft palate were 2.4 times higher with exposure to ondansetron during the first trimester (n = 55) vs unexposed pregnancies (n = 4479); however, the risk for cleft lip, hypospadias, or neural tube defects was similar in both groups.

Australian researchers[7] compared 251 pregnant women exposed to ondansetron from 2002 to 2005 with 96,717 unexposed pregnant women during this same period. Although not statistically significant, a 20% increased risk for a major birth defect among infants exposed to ondansetron during the first trimester was reported. The estimate was based on a low incidence of birth defects and was imprecise, with a wide confidence interval (CI) (odds ratio, 1.2; CI, 0.6-2.2).

Danish researchers[8] reported results of large cohort study evaluating 1970 pregnancies exposed to ondansetron during the first trimester from 2004 to 2011. Data from the Medical Birth Registry and National Patient Register in Denmark were gathered, and pregnant women receiving ondansetron during the first trimester were matched in a 1:4 ratio with unexposed pregnant women. One half of the prescriptions for ondansetron were filled before 10 weeks of gestation and one half were filled after. Compared with unexposed pregnancies, ondansetron was not associated with an increased risk for miscarriage, stillbirth, major birth defect, or preterm delivery. Most ondansetron exposure occurred in the second half of the first trimester, which may limit the applicability of these results to ondansetron exposure in the first few weeks of gestation.

Another group of Danish researchers,[9] using the same Medical Birth Registry and National Patient Register, evaluated the teratogenic effects of ondansetron exposure during the first trimester using 1997-2010 data. Of the 897,018 births in this timeframe, prescription records suggested that 1248 women were exposed to ondansetron. The odds of fetal heart malformation were two times higher in infants of women exposed to ondansetron compared with unexposed women; the risk for major birth defects overall was similar.

Swedish researchers[10] used the Swedish Medical Birth Register and Swedish Register of Prescribed Drugs to gather data on pregnancies and exposure to ondansetron early in pregnancy. During the period between 1998 and 2012, 1349 women received ondansetron in early pregnancy. Ondansetron exposure was not associated with an increased risk for severe birth defects; however, the odds of general heart defects were 1.6 times higher, and the odds of heart septum defects were 2.1 times higher.

Overall, the risks associated with ondansetron exposure during the first trimester of pregnancy remain unclear. Most observational research suggests that ondansetron is unlikely to increase the risk for miscarriage, stillbirth, or major birth defects.[2,6,7,8,9,10] The few studies evaluating the effect of ondansetron on specific birth defects associate ondansetron exposure early in pregnancy with a small but significant risk for cleft palate and heart defects.[2,9,10]

Ondansetron is not recommended by current guidelines as a first-line option for nausea and vomiting in pregnancy.[11,12] Initial treatments are lifestyle and dietary modifications. If drug therapy is required, doxylamine/pyridoxine (Diclegis®) is FDA-approved and guideline-endorsed for the treatment of nausea and vomiting in pregnancy.[11,12] Given the current evidence, ondansetron should be avoided in the first trimester of pregnancy unless other treatments are ineffective.

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