Mothers who took ondansetron (Zofran) in the first trimester of pregnancy were generally not more likely to have children with congenital malformations, although a small increased risk of oral clefts was observed, according to a retrospective cohort study.
Compared with unexposed peers, women prescribed the medication for morning sickness in the first trimester had numerically more pregnancies result in children with fetal malformations, yet this was statistically significant only for oral clefts:
- Cardiac malformation: 84.4 vs 94.4 per 10,000 births (adjusted RR 0.99, 95% CI 0.93-1.06)
- Oral clefts: 11.1 vs 14.0 per 10,000 births (adjusted RR 1.24, 95% CI 1.03-1.48)
- Any congenital malformation: 313.5 vs 370.4 per 10,000 births (adjusted RR 1.01, 95% CI 0.98-1.05)
Results were the same looking at other antiemetics taken for nausea and vomiting, namely metoclopramide, promethazine, and vitamin B6, reported Krista Huybrechts, PhD, of Brigham and Women’s Hospital in Boston, and colleagues in JAMA.
They based their study on the nationwide Medicaid Analytic eXtract, which provided information on the pregnancies of more than 1.5 million Medicaid patients in 2000-2013. Excluded were pregnancies with chromosomal abnormalities and those exposed to teratogenic medications.
From prescription data, it turned out that 4.9% of pregnancies were exposed to ondansetron during the first trimester, the crucial period of fetal organ formation. Exposed women were more likely to be white, to have a psychiatric or neurological condition, to smoke, and to have a comorbid illness.
History has given morning sickness drugs somewhat of a bad reputation, such as the infamous birth defects linked to thalidomide users and the fetal malformations allegedly associated with combination vitamin B6/doxylamine (Diclegis).
Recently, however, the literature has been more mixed, as some studies are finding no adverse effects of antiemetic use. In 2015, the American College of Obstetricians and Gynecologists (ACOG) concluded that there are insufficient data on fetal safety with ondansetron exposure and called for further study.
Despite the main findings by Huybrechts and colleagues, ondansetron exposure still may not be completely benign.
The investigators acknowledged that they had no idea if the women actually took the medication after getting the prescription filled. The retrospective study could also have been affected by residual confounding, and has limited generalizability given its focus on a more disadvantaged population on Medicaid.
Additionally, two fetal cardiac malformations had been linked to ondansetron in unadjusted analyses: ventricular septal defects (RR 1.14, 95% CI 1.04-1.27) and secundum atrial septal defects (RR 1.37, 95% CI 1.19-1.57). Moreover, an exploratory analysis showed an uptick in ear malformations among ondansetron users (2.4 vs 3.8 per 10,000 births, adjusted RR 1.64, 95% CI 1.16-2.33).
Still, the study “provides some reassurance” regarding the safety of this commonly used medication, wrote David Haas, MD, of Indiana University School of Medicine in Indianapolis, in an accompanying editorial.
The ACOG treatment algorithm does not place ondansetron as a first-line drug for nausea and vomiting (recommending instead pyridoxine with or without doxylamine as first-line pharmacotherapy).
“However, it is one of the most commonly used agents in practice. This may be because of its different formulations, including an oral dissolving tablet, and its perceived effectiveness. Thus, it is important that clinicians and pregnant women have accurate safety information about its use during pregnancy,” Haas said.
The study by Huybrechts’ group, he concluded, “documents clearly that while the adjusted relative risk of oral clefts was elevated, the absolute risk increase is very low.”
The study was supported by a grant from the National Institute of Child Health and Human Development.
Huybrechts disclosed support (institutional) from Eli Lilly, Pfizer, GlaxoSmithKline, and Boehringer-Ingelheim.
Haas disclosed no relevant relationships with industry.