Influenza, and not the antiviral treatment for it, is responsible for increased neuropsychiatric risks in pediatric patients, new research suggested.
The risk for these events was about 50% lower in children treated with oseltamivir (Tamiflu), the most widely prescribed antiviral for influenza, compared to no treatment, investigators found.
Oseltamivir currently carries a warning label about increased risk for neuropsychiatric events, including seizure. However, the label is based on low-quality studies, lead investigator James W. Antoon, MD, PhD, assistant professor of pediatrics at Vanderbilt University Medical Center, Nashville, Tennessee, told Medscape Medical News.
The findings of the study, which Antoon said is the most rigorous of its kind to date, suggest that the warning label may no longer be necessary.
“Our main finding was that oseltamivir prevents neuropsychiatric events and that neuropsychiatric events during periods of influenza is really driven by influenza itself,” he said. “This influenza antiviral is safe and effective and should be used as early as possible in the course of influenza illness.”
Definitive Answer?
Oseltamivir is currently the most commonly prescribed antiviral for influenza for both children and adults and is particularly beneficial during the illness’ early stages.
The FDA added the warning label to the drug packaging after safety concerns were raised in 2006. However, the researchers noted that “it is important to note that these warnings were placed on the basis of case reports rather than studies on associated risks for these events.”
No randomized study to date has shown a significant association between the medication and neuropsychiatric events in pediatric patients, and there have been conflicting results from observational studies, they added.
Antoon said he first became aware of the warning during his medical residency. However, upon reviewing the studies examining the link, he found that there was little high-quality research on the topic.
Once he began practicing, he noted that parents frequently expressed concerns about these risks.
“Even for children at high risk for influenza complications, who would benefit from treatment, parents would decline it. So we chose to do this study to be the definitive answer of whether oseltamivir is associated with neuropsychiatric events or is it the underlying influenza that’s really driving the alterations in children’s behavior,” Antoon said.
The retrospective cohort study assessed data from influenza seasons in 2016-2017 and 2019-2020. It included 692,295 children and adolescents aged 5-17 years (median age, 11 years; 50.3% girls) enrolled in Tennessee Medicaid.
Each person-day of follow-up was stratified into one of five exposure groups: no exposure (to influenza or oseltamivir), untreated influenza (up to 10 days after diagnosis), treated influenza, posttreatment (time between oseltamivir completion to end of influenza period), and influenza prophylaxis (oseltamivir treatment without influenza).
The primary outcome was any neuropsychiatric event that required hospitalization.
Helpful, Not Harmful
Results showed that 129,134 individuals had 151,401 influenza episodes, and 66.7% of those episodes were treated with oseltamivir. Among the participants deemed to be at high risk for influenza-related complications, 60.1% received oseltamivir treatment.
There were 898 neurologic and 332 psychiatric events during 19,688,320 person-weeks of follow-up.
The most common serious neuropsychiatric adverse events were mood disorders (36.3%) and suicidal or self-harm behaviors (34.2%), followed by seizures (13.7%). The overall incidence rate ratio (IRR) was 6.25 per 100,000 person-weeks for a serious neuropsychiatric event.
The risk for these events was significantly lower during periods where influenza was treated with oseltamivir (adjusted IRR, 0.53; 95% CI, 0.33-0.88) and during posttreatment (adjusted IRR, 0.42; 95% CI, 0.24-0.74) than during untreated influenza.
“Sensitivity analyses suggest misclassification or unmeasured confounding would not explain these findings,” the investigators wrote.
Subanalyses showed that the adjusted IRRs for neurologic and psychiatric events separately in the treated group were 0.45 (95% CI, 0.25-0.83) and 0.80 (95% CI, 0.34-1.88), respectively.
Antoon noted that neurologic events are more common than psychiatric events in young patients and that the lower number of those outcomes overall may have led to a smaller decrease in psychiatric events.
“All of the results together suggest that oseltamivir is not associated with neuropsychiatric events and, in fact, may be helpful in preventing these events in children,” Antoon said.
‘Double-Edged Sword’
Commenting for Medscape Medical News, Soonjo Hwang, MD, associate professor of psychiatry and from the Child and Adolescent Psychiatry Department at the University of Nebraska Medical Center, Omaha, Nebraska, noted that although the study provides important and reassuring information, he wouldn’t necessarily say it provides the definitive answer on this topic.
Hwang, who was not involved with the research, noted that the study was a retrospective cohort review with several confounding variables that were not controlled for, including various socioeconomic factors and how amenable the parents were to the treatment options.
Additionally, he pointed out that medication warning labels for pediatric populations are often based on case reports because of the difficulty in conducting clinical trials in an ethical way in such a young group.
“It’s kind of a double-edged sword. You want to use the medicine as safely as possible, but you also don’t want to limit the access to treatment options just because there are no sufficient data available,” Hwang said.
So what should clinicians do while waiting for additional research?
“I think, as a clinician, you need to have an informed conversation with parents of young children about the risk and benefit of any treatment option and make the best judgement you can case-by-case. But, indeed, we really need more clinical trials to make sure we’re using them in a safe way but also in an effective way,” he concluded.
The study was funded in part by the US National Institute for Allergy and Infectious Diseases and the National Institute of Child Health and Human Development. Antoon reported having received personal fees from serving on an AstraZeneca Scientific Advisory Board. A full list of relevant conflicts for the other investigators are provided in the original article. Hwang reported having no relevant financial relationships.