Nausea and vomiting of pregnancy (NVP) affects up to 80% of pregnant women, most commonly between 5 and 18 weeks of gestation. In addition, its extreme form, hyperemesis gravidarum, affects less than 3% of pregnancies.1 Certainly with hyperemesis gravidarum, and oftentimes with less severe NVP, pharmacologic treatment is desired or required. One of the choices for such treatment has been ondansetron, a 5-HT3 receptor antagonist, which has been used off label for NVP and is now available in generic form. However, there have been concerns raised regarding the fetal safety of this medication, last reviewed in Ob.Gyn. News by Gideon Koren, MD, in.
Since then, the escalating use of ondansetron in the United States has been described using a large dataset covering 2.3 million, predominantly commercially insured, pregnancies that resulted in live births from 2001 to 2015.1 Over that period of time, any outpatient pharmacy dispensing of an antiemetic in pregnancy increased from 17.0% in 2001 to 27.2% in 2014. That increase was entirely accounted for by a dramatic rise in oral ondansetron use beginning in 2006. By 2014, 22.4% of pregnancies in the database had received a prescription for ondansetron.
There have been two studies that have suggested an increased risk in specific major birth defects with first-trimester ondansetron use. The first, published in 2012, used data from the National Birth Defects Prevention case control study from 1997 to 2004 to examine risks with NVP and its treatments for the most common noncardiac defects in the dataset. These included cleft lip with or without cleft palate, cleft palate alone, neural tube defects, and hypospadias. NVP itself was not associated with any increased risks for the selected defects. In contrast, ondansetron was associated with an increased risk for cleft palate alone based on seven exposed cases (adjusted odds ratio, 2.37; 95% confidence interval, 1.18-4.76).2
A second study published in 2014 used data from the Swedish Medical Birth Register from 1998 to 2012 to identify 1,349 infants whose mothers reported taking ondansetron in early pregnancy. While no overall increased risk of major birth defects was found with early pregnancy ondansetron use, compared with no such use, there was a significant increased risk noted for cardiovascular defects, particularly cardiac septum defects (any cardiac defect OR, 1.62; 95% CI, 1.04-2.14; cardiac septum defects risk ratio, 2.05; 95% CI, 1.19-3.28).3 No cases of cleft palate were reported among exposed cases in that study.
In contrast, in another study, Danish National Birth Cohort data on 608,385 pregnancies from 2004 to 2011 were used to compare major birth defect outcomes among 1,233 women exposed to ondansetron in the first trimester with those of 4,392 unexposed women.4 The birth prevalence of any major birth defect was identical (2.9%) in both exposed and unexposed groups (adjusted prevalence OR, 1.12; 95% CI, 0.69-1.82). No cases of cleft palate were reported among exposed cases and the crude OR for any cardiac defect approximated the null (1.04; 95% CI, 0.52-1.95). Two other smaller or less well-designed studies did not support an increased risk for major birth defects overall (; Einarson et al. 2004Aug 23. ).