Congenital malformations not increased after maternal ondansetron use

Last Updated: 2018-12-19

By Will Boggs MD

NEW YORK (Reuters Health) - Maternal first-trimester use of ondansetron for nausea and vomiting is not linked with congenital malformations, although there is a small increased risk of oral clefts, according to a retrospective study of women enrolled in Medicaid.

"Prior evidence had suggested a potential doubling in the risk of cardiac malformations and oral clefts associated with ondansetron use," said Dr. Krista F. Huybrechts of Brigham and Women's Hospital in Boston.

"In that regard, it is important that in the context of this large study with careful control for confounding adjustment, we did not observe an association between ondansetron and cardiac malformation or congenital malformations overall, and although we cannot exclude a small increased risk of oral clefts, if present, the risk increase is smaller than what has previously been suggested," she told Reuters Health by email.

For the study, published December 18 in JAMA, Dr. Huybrechts's team analyzed data from the nationwide Medicaid Analytic eXtract from 2000 through 2013.

Out of more than 1.8 million pregnancies, 4.9% were exposed to ondansetron during the first trimester.

The risk for any congenital malformation was 370.4 per 10,000 pregnancies exposed to ondansetron versus 313.5 per 10,000 unexposed pregnancies.

The risk of cardiac malformations was 94.4 per 10,000 ondansetron-exposed pregnancies (versus 84.4 per 10,000 among unexposed pregnancies), and the risk of oral clefts was 14.0 per 10,000 ondansetron-exposed pregnancies (versus 11.1 per 10,000 unexposed pregnancies).

After adjusting for other variables, ondansetron use was not associated with a significant increase in overall congenital malformations or in cardiac malformations.

In contrast, there was a statistically significant increase in the risk of oral clefts associated with first-trimester ondansetron use that amounted to 2.7 extra cases per 10,000 births.

Results were similar when women who took other antiemetics were used as the reference group instead of women unexposed to ondansetron.

Since Medicaid covers the medical expenses for about half of all pregnancies in the U.S., the researchers note, these results should be generalizable to the broader Medicaid population, as well as to commercially insured pregnant women in the U.S. and pregnant women in other countries.

"Our findings suggest that ondansetron does not meaningfully increase the risk of congenital malformations," Dr. Huybrechts said. "They suggest that the current approach to the treatment of nausea and vomiting, which commonly includes ondansetron, is safe."

Dr. David M. Haas from Indiana University School of Medicine, in Indianapolis, who wrote a linked editorial, told Reuters Health by email, "I believe that this study helps reassure clinicians that we can continue to prescribe ondansetron for women with severe nausea and vomiting in pregnancy who are unresponsive to the typical first-line therapies."

"Nausea and vomiting of pregnancy is complex and sometimes difficult to treat," he said. "It is common in practice for women to be on multiple therapies at the same time for this. Thus, we need to have risk-benefit conversations with all patients, including pregnant women, about the medications we prescribe."

Dr. Marlena S. Fejzo of the University of California, Los Angeles, and the University of Southern California, Los Angeles, who earlier reported results suggesting ondansetron was not teratogenic, told Reuters Health by email, "Hyperemesis gravidarum can be associated with poor maternal, fetal, and child outcomes, so the fact that 1.4 out of 1,000 women who took ondansetron in the first trimester had a baby with cleft palate compared to 1.1 out of 1,000 women who did not take ondansetron in the first trimester does not seem like a reason to change current prescription practices, although I would recommend discussing the risk in detail with the patient because people vary greatly in their comfort levels with respect to risk."

"It would be helpful in the future to determine exactly which week of first-trimester exposure is associated with the increase in risk of oral clefts," she said. "Then patients could avoid exposure specifically during that time."

"Society would benefit greatly from a national database and a requirement of providers to report exposure timing and outcomes for off-label prescriptions to pregnant women," Dr. Fejzo added. "With so many women taking ondansetron in the U.S., we could have a final answer on this very quickly. The answer is out there, and we owe it to pregnant women and their children to get it."

Dr. Melissa Lavecchia of the University of Alberta, in Edmonton, Canada, who recently undertook a systematic review of the risk of congenital malformations associated with ondansetron use in pregnancy, said, "There remains insufficient evidence to clearly link maternal ondansetron use to congenital malformations. Women should continue to be counseled on the risks and benefits of ondansetron use in early pregnancy according to the available literature."

"Because there exists other medications with proven safety profiles, ondansetron should continue to be used as a third-line agent, as outlined in ACOG's algorithm of therapeutic treatment of nausea and vomiting of pregnancy," she told Reuters Health by email. "However, when other options have been exhausted, this study provides reassurance to both patients and clinicians that ondansetron, despite a possible small increase risk for oral clefs, is likely safe in pregnancy."

SOURCE: https://bit.ly/2EByIfx

JAMA 2018.