A slew of investigations over the years have found varying rates of birth defects among pregnant women taking ondansetron, from no cases of cleft palate in one study to a twofold increased risk in another, leaving a murky landscape for emergency physicians trying to alleviate these patients' nausea and vomiting.
Despite the most recent study—a massive JAMA report of nearly 89,000 exposures that revealed no link between ondansetron and cardiac defects or congenital malformations overall but some oral clefts—the best course of action is a stepwise approach advocated by the American College of Obstetrics and Gynecology.
Nausea and vomiting affect up to 75 percent of pregnant women, most commonly in the first trimester. Presentations to the emergency department for this condition are frequent, and emergency physicians can rapidly evaluate for metabolic abnormalities or clinical deterioration, which may indicate the more severe syndrome of hyperemesis gravidarum while providing safe and effective symptomatic care. Antiemetics and intravenous fluids are routinely administered to reverse a spiral of dehydration, ketosis, and misery. Unfortunately, concerns about the safety of ondansetron, a 5-HT3 receptor antagonist, have led to confusion in the approach to an otherwise straightforward clinical scenario.
A team of public health researchers published a case-control study in 2012 examining associations between commonly used medications during pregnancy and the development of congenital malformations. Using a simple survey-based technique, the team identified no overall increased risk of birth defects among patients taking ondansetron, but a subgroup analysis detected a twofold increased risk of cleft palate, an observation borne from just 55 total exposures, 11 of which developed a defect. (Birth Defects Res A Clin Mol Teratol 2012;94:22; http://bit.ly/2HmiHNi.) A second study published two years later examined a much larger relevant cohort from nested Swedish databases. A single case of oral cleft was reported from 1349 ondansetron exposures, and a small increased risk of cardiac septum defects was found, though no overall increased risk of major birth defects was found with early pregnancy ondansetron use. (Reprod Toxicol 2014;50:134; http://bit.ly/2DpgD30.)
More studies followed, including a Danish trial of similar size and methodology to their Swedish colleagues, which not only failed to identify an increased risk of oral clefts, cardiac defects, or any other major birth defects, but in fact reported no cases of cleft palate. (N Engl J Med 2013;28;368:814; http://bit.ly/2Cy7zr2.) An administrative data linkage study of the same year explored exposures across all three trimesters (well after organogenesis), but saw no increased risk of birth defects among women exposed to ondansetron in the first trimester. Despite the statistical back-and-forth, specialty societies and concerned obstetricians began to warn against first-line use of ondansetron. Malpractice lawyers and predatory websites flourished, evidentiary equipoise be damned.
A study published at the end of 2018 in JAMA finally sheds light on this. Using an enormous Medicaid dataset, these researchers examined nearly two million pregnancies, and considered women exposed to ondansetron if they filled at least one prescription for the drug during the first trimester, identifying 88,467 exposures, an order of magnitude greater than every other previous investigation combined. Their results are likely to define this practice area for the foreseeable future, and are critically important for the frontline emergency physician. (JAMA 2018;320:2429.)
In unadjusted analyses, exposure to ondansetron was distinctly and significantly associated with the development of cardiac malformations, oral clefts, and any and all congenital malformations. Nearly all of these associations disappeared, however, after stratification and balancing for confounding characteristics—concomitant medication use, race, age, and comorbid conditions. The properly balanced analysis revealed no linkage between ondansetron use and the development of cardiac defects or congenital malformations overall. Critically, however, a small increased risk of the development of oral clefts remained, corresponding to an additional 2.7 oral clefts per 10,000 births.
The conclusion seems straightforward, but is more than likely anything but. This study is almost certain to be held up by ondansetron supporters and skeptics alike, with the results demonstrating that the drug does not meaningfully increase the risk of congenital malformations, though the higher incidence of oral clefts is incontrovertible. Providing ondansetron in clinical practice should occur in the context of shared decision-making with patients, and these results ought to reassure pregnant women who need to make a risk-benefit decision regarding treatment.
In truth, though, this trial should have little impact on the ED management of nausea and vomiting in pregnancy. The use of ondansetron for this patient population has exploded since 2001 despite no compelling data of superior efficacy over first-line therapies or low-level evidence that more traditional agents work just as well, if not better. (Cochrane Database Syst Rev 2010;8:CD007575; http://bit.ly/2W6Um1o.)
The American College of Obstetrics and Gynecology has published guidelines for years on pharmacologically managing nausea and vomiting in pregnancy, recommending a stepwise approach, starting with pyridoxine (vitamin B6) and doxylamine and then—depending on the presence or absence of dehydration—adding intravenous fluids and agents such as promethazine, prochlorperazine, or metoclopramide before proceeding to therapies like ondansetron and methylprednisolone. (Obstet Gynecol 2018 Jan;131:e15.) This measured and incremental approach represents an evidence-based and effective strategy that allows for all possible useful therapies while keeping maternal and fetal safety paramount.
Ondansetron has proven itself to be generally but not completely safe in these patients, but has yet to show its superiority over traditional agents. As emergency physicians and pregnant women engage in collaborative efforts to provide effective symptom management, ondansetron should remain relegated to its important but auxiliary role.
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Dr. Pescatore is the director of emergency medicine research for the Crozer-Keystone Health System in Chester, PA. He is also the host with Ali Raja, MD, of the podcast EMN Live, which focuses on hot topics in emergency medicine: http://bit.ly/EMNLive. Follow him on Twitter @Rick_Pescatore, and read his past columns at http://bit.ly/EMN-Pescatore.Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.